Method of diagnosing neoplasms - ii

ABSTRACT

The present invention relates generally to nucleic acid molecules in respect of which changes to the DNA or to the RNA or protein expression profiles are indicative of the onset, predisposition to the onset and/or progression of a neoplasm. More particularly, the present invention is directed to nucleic acid molecules in respect of which changes to the DNA or to the RNA or protein expression profiles are indicative of the onset and/or progression of a large intestine neoplasm, such as an adenoma or an adenocarcinoma. The DNA or the expression profiles of the present invention are useful in a range of applications including, but not limited to, those relating to the diagnosis and/or monitoring of colorectal neoplasms, such as colorectal adenocarcinomas. Accordingly, in a related aspect the present invention is directed to a method of screening a subject for the onset, predisposition to the onset and/or progression of a neoplasm by screening for modulation in the DNA or the RNA or protein expression profile of one or more nucleic acid molecule markers.

FIELD OF THE INVENTION

The present invention relates generally to nucleic acid molecules inrespect of which changes to the DNA or to the RNA or protein expressionprofiles are indicative of the onset, predisposition to the onset and/orprogression of a neoplasm. More particularly, the present invention isdirected to nucleic acid molecules in respect of which changes to theDNA or to the RNA or protein expression profiles are indicative of theonset and/or progression of a large intestine neoplasm, such as anadenoma or an adenocarcinoma. The DNA or the expression profiles of thepresent invention are useful in a range of applications including, butnot limited to, those relating to the diagnosis and/or monitoring ofcolorectal neoplasms, such as colorectal adenocarcinomas. Accordingly,in a related aspect the present invention is directed to a method ofscreening a subject for the onset, predisposition to the onset and/orprogression of a neoplasm by screening for modulation in the DNA or theRNA or protein expression profile of one or more nucleic acid moleculemarkers.

BACKGROUND OF THE INVENTION

Bibliographic details of the publications referred to by author in thisspecification are collected alphabetically at the end of thedescription.

The reference in this specification to any prior publication (orinformation derived from it), or to any matter which is known, is not,and should not be taken as an acknowledgment or admission or any form ofsuggestion that that prior publication (or information derived from it)or known matter forms part of the common general knowledge in the fieldof endeavour to which this specification relates.

Adenomas are benign tumours, or neoplasms, of epithelial origin whichare derived from glandular tissue or exhibit clearly defined glandularstructures. Some adenomas show recognisable tissue elements, such asfibrous tissue (fibroadenomas) and epithelial structure, while others,such as bronchial adenomas, produce active compounds that might giverise to clinical syndromes.

Adenomas may progress to become an invasive neoplasm and are then termedadenocarcinomas. Accordingly, adenocarcinomas are defined as malignantepithelial tumours arising from glandular structures, which areconstituent parts of many organs of the body. The term adenocarcinoma isalso applied to tumours showing a glandular growth pattern. Thesetumours may be sub-classified according to the substances that theyproduce, for example mucus secreting and serous adenocarcinomas, or tothe microscopic arrangement of their cells into patterns, for examplepapillary and follicular adenocarcinomas. These carcinomas may be solidor cystic (cystadenocarcinomas). Each organ may produce tumours showinga variety of histological types, for example the ovary may produce bothmucinous and cystadenocarcinoma.

Adenomas in different organs behave differently. In general, the overallchance of carcinoma being present within an adenoma (i.e. a focus ofcancer having developed within a benign lesion) is approximately 5%.However, this is related to size of an adenoma. For instance, in thelarge bowel (colon and rectum specifically) occurrence of a cancerwithin an adenoma is rare in adenomas of less than 1 centimeter. Such adevelopment is estimated at 40 to 50% in adenomas which are greater than4 centimeters and show certain histopathological change such as villouschange, or high grade dysplasia. Adenomas with higher degrees ofdysplasia have a higher incidence of carcinoma. In any given colorectaladenoma, the predictors of the presence of cancer now or the futureoccurrence of cancer in the organ include size (especially greater than9 mm) degree of change from tubular to villous morphology, presence ofhigh grade dysplasia and the morphological change described as “serratedadenoma”. In any given individual, the additional features of increasingage, familial occurrence of colorectal adenoma or cancer, male gender ormultiplicity of adenomas, predict a future increased risk for cancer inthe organ—so-called risk factors for cancer. Except for the presence ofadenomas and its size, none of these is objectively defined and allthose other than number and size are subject to observer error and toconfusion as to precise definition of the feature in question. Becausesuch factors can be difficult to assess and define, their value aspredictors of current or future risk for cancer is imprecise.

Once a sporadic adenoma has developed, the chance of a new adenomaoccurring is approximately 30% within 26 months.

Colorectal adenomas represent a class of adenomas which are exhibitingan increasing incidence, particularly in more affluent countries. Thecauses of adenoma, and of progression to adenocarcinoma, are still thesubject of intensive research. To date it has been speculated that inaddition to genetic predisposition, environmental factors (such as diet)play a role in the development of this condition. Most studies indicatethat the relevant environmental factors relate to high dietary fat, lowfibre, low vegetable intake, smoking, obesity, physical inactivity andhigh refined carbohydrates.

Colonic adenomas are localised areas of dysplastic epithelium whichinitially involve just one or several crypts and may not protrude fromthe surface, but with increased growth in size, usually resulting froman imbalance in proliferation and/or apoptosis, they may protrude.Adenomas can be classified in several ways. One is by their grossappearance and the major descriptors include degrees of protrusion: flatsessile (i.e. protruding but without a distinct stalk) or pedunculated(i.e. having a stalk). Other gross descriptors include actual size inthe largest dimension and actual number in the colon/rectum. While smalladenomas (less than say 5 or 10 millimeters) exhibit a smooth tansurface, pedunculated and especially larger adenomas tend to have acobblestone or lobulated red-brown surface. Larger sessile adenomas mayexhibit a more delicate villous surface. Another set of descriptorsinclude the histopathological classification; the prime descriptors ofclinical value include degree of dysplasia (low or high), whether or nota focus of invasive cancer is present, degree of change from tubulargland formation to villous gland formation (hence classification istubular, villous or tubulovillous), presence of admixed hyperplasticchange and of so-called “serrated” adenomas and its subgroups. Adenomascan be situated at any site in the colon and/or rectum although theytend to be more common in the rectum and distal colon. All of thesedescriptors, with the exception of number and size, are relativelysubjective and subject to interobserver disagreement.

The various descriptive features of adenomas are of value not just toascertain the neoplastic status of any given adenomas when detected, butalso to predict a person's future risk of developing colorectal adenomasor cancer. Those features of an adenoma or number of adenomas in anindividual that point to an increased future risk for cancer orrecurrence of new adenomas include: size of the largest adenoma(especially 10 mm or larger), degree of villous change (especially atleast 25% such change and particularly 100% such change), high gradedysplasia, number (3 or more of any size or histological status) orpresence of serrated adenoma features. None except size or number isobjective and all are relatively subjective and subject to interobserverdisagreement. These predictors of risk for future neoplasia (hence“risk”) are vital in practice because they are used to determine therate and need for and frequency of future colonoscopic surveillance.More accurate risk classification might thus reduce workload ofcolonoscopy, make it more cost-effective and reduce the risk ofcomplications from unnecessary procedures.

Adenomas are generally asymptomatic, therefore rendering difficult theirdiagnosis and treatment at a stage prior to when they might developinvasive characteristics and so became cancer. It is technicallyimpossible to predict the presence or absence of carcinoma based on thegross appearance of adenomas, although larger adenomas are more likelyto show a region of malignant change than are smaller adenomas. Sessileadenomas exhibit a higher incidence of malignancy than pedunculatedadenomas of the same size. Some adenomas result in blood loss whichmight be observed or detectable in the stools; while sometimes visibleby eye, it is often, when it occurs, microscopic or “occult”. Largeradenomas tend to bleed more than smaller adenomas. However, since bloodin the stool, whether overt or occult, can also be indicative ofnon-adenomatous conditions, the accurate diagnosis of adenoma isrendered difficult without the application of highly invasive proceduressuch as colonoscopy combined with tissue acquisition by either removal(i.e. polypectomy) or biopsy and subsequent histopathological analysis.

Accordingly, there is an on-going need to elucidate the causes ofadenoma and to develop more informative diagnostic protocols or aids todiagnosis that enable one to direct colonoscopy at people more likely tohave adenomas. These adenomas may be high risk, advanced or neither ofthese, in particular protocols which will enable the rapid, routine andaccurate diagnosis of adenoma. Furthermore, it can be difficult aftercolonoscopy to be certain that all adenomas have been removed,especially in a person who has had multiple adenomas. An accuratescreening test may minimise the need to undertake an early secondcolonoscopy to ensure that the colon has been cleared of neoplasms.Accordingly, the identification of molecular markers for adenomas wouldprovide means for understanding the cause of adenomas and cancer,improving diagnosis of adenomas including development of usefulscreening tests, elucidating the histological stage of an adenoma,characterising a patient's future risk for colorectal neoplasia on thebasis of the molecular state of an adenoma and facilitating treatment ofadenomas.

To date, research has focused on the identification of gene mutationswhich lead to the development of colorectal neoplasms. In work leadingup to the present invention, however, it has been determined thatchanges in the DNA or the RNA or protein expression profiles of geneswhich are also expressed in healthy individuals are indicative of thedevelopment of neoplasms of the large intestine, such as adenomas andadenocarcinomas. It has been further determined that in relation toneoplasms of the large intestine, diagnosis can be made based onscreening for one or more of a panel of these differentially expressedgenes. In a related aspect, it has still further been determined that tothe extent that neoplastic tissue has been identified either by themethod of the invention or by some other method, the present inventionprovides still further means of characterising that tissue as an adenomaor a cancer. In yet another aspect, it has been determined that aproportion of these genes are characterised by gene expression whichoccurs in the context of non-neoplastic tissue but not in the context ofneoplastic tissue, thereby facilitating the development of qualitativeanalyses which do not require a relative analysis to be performedagainst a non-neoplastic or normal control reference level. Accordingly,the inventors have identified a panel of genes which facilitate thediagnosis of adenocarcinoma and adenoma development and/or themonitoring of conditions characterised by the development of these typesof neoplasms.

SUMMARY OF THE INVENTION

Throughout this specification and the claims which follow, unless thecontext requires otherwise, the word “comprise”, and variations such as“comprises” and “comprising”, will be understood to imply the inclusionof a stated integer or step or group of integers or steps but not theexclusion of any other integer or step or group of integers or steps.

As used herein, the term “derived from” shall be taken to indicate thata particular integer or group of integers has originated from thespecies specified, but has not necessarily been obtained directly fromthe specified source. Further, as used herein the singular forms of “a”,“and” and “the” include plural referents unless the context clearlydictates otherwise.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs.

The subject specification contains amino acid and nucleotide sequenceinformation prepared using the programme PatentIn Version 3.4, presentedherein after the bibliography. Each amino acid and nucleotide sequenceis identified in the sequence listing by the numeric indicator <210>followed by the sequence identifier (eg. <210>1, <210>2, etc). Thelength, type of sequence (amino acid, DNA, etc.) and source organism foreach sequence is indicated by information provided in the numericindicator fields <211>m <212> and <213>, respectively. Amino acid andnucleotide sequences referred to in the specification are identified bythe indicator SEQ ID NO: followed by the sequence identifier (eg. SEQ IDNO:1, SEQ ID NO: 2, etc). The sequence identifier referred to in thespecification correlates to the information provided in numericindicator field <400> in the sequence listing, which is followed by thesequence identifier (eg. <400>1, <400>2, etc). That is SEQ ID NO: 1 asdetailed in the specification correlates to the sequence indicated as<400>1 in the sequence listing.

One aspect of the present invention is directed to a method of screeningfor the onset or predisposition to the onset of a large intestineneoplasm in an individual, said method comprising assessing the level ofexpression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

200600_at 210133_at 227235_at 200621_at 210139_s_at 227265_at 200795_at210298_x_at 227404_s_at 200799_at 210299_s_at 227529_s_at 200845_s_at210302_s_at 227561_at 200859_x_at 210495_x_at 227623_at 200897_s_at210517_s_at 227662_at 200974_at 210764_at 227705_at 200986_at210809_s_at 227727_at 201041_s_at 210946_at 227826_s_at 201058_s_at210982_s_at 227827_at 201061_s_at 211161_s_at 228202_at 201069_at211548_s_at 228504_at 201105_at 211596_s_at 228507_at 201137_s_at211643_x_at 228640_at 201141_at 211644_x_at 228706_s_at 201150_s_at211645_x_at 228707_at 201289_at 211671_s_at 228750_at 201300_s_at211696_x_at 228766_at 201324_at 211719_x_at 228846_at 201348_at211798_x_at 228854_at 201426_s_at 211813_x_at 228885_at 201427_s_at211848_s_at 229530_at 201438_at 211889_x_at 229839_at 201496_x_at211896_s_at 230087_at 201497_x_at 211959_at 230264_s_at 201539_s_at211964_at 230788_at 201540_at 211985_s_at 230830_at 201616_s_at211990_at 231120_x_at 201617_x_at 211991_s_at 231579_s_at 201645_at212077_at 231773_at 201667_at 212091_s_at 234764_x_at 201739_at212097_at 234987_at 201743_at 212136_at 236300_at 201744_s_at 212158_at236313_at 201842_s_at 212185_x_at 242317_at 201852_x_at 212192_at200884_at 201858_s_at 212195_at 201495_x_at 201859_at 212230_at202266_at 201865_x_at 212233_at 202350_s_at 201893_x_at 212265_at202731_at 201920_at 212288_at 202741_at 201957_at 212386_at 202742_s_at202007_at 212387_at 202768_at 202037_s_at 212397_at 202838_at202069_s_at 212414_s_at 203058_s_at 202133_at 212419_at 203060_s_at202222_s_at 212464_s_at 203240_at 202242_at 212667_at 203296_s_at202274_at 212671_s_at 203343_at 202283_at 212713_at 203474_at202291_s_at 212730_at 203638_s_at 202388_at 212764_at 203963_at202555_s_at 212859_x_at 204018_x_at 202620_s_at 212956_at 204034_at202686_s_at 213068_at 204036_at 202746_at 213071_at 204130_at202760_s_at 213428_s_at 204388_s_at 202766_s_at 213509_x_at 204389_at202888_s_at 213624_at 204508_s_at 202920_at 213746_s_at 204532_x_at202953_at 213891_s_at 204607_at 202957_at 214027_x_at 204673_at202992_at 214038_at 204818_at 202994_s_at 214091_s_at 204895_x_at202995_s_at 214142_at 204897_at 203000_at 214414_x_at 205112_at203001_s_at 214505_s_at 205259_at 203066_at 214677_x_at 205403_at203131_at 214696_at 205480_s_at 203305_at 214752_x_at 205554_s_at203382_s_at 214768_x_at 205593_s_at 203477_at 214777_at 205892_s_at203645_s_at 215049_x_at 205929_at 203680_at 215076_s_at 206000_at203729_at 215118_s_at 206094_x_at 203748_x_at 215176_x_at 206262_at203766_s_at 215193_x_at 206377_at 203881_s_at 215382_x_at 206385_s_at203908_at 215388_s_at 206664_at 203913_s_at 215657_at 207126_x_at203914_x_at 216207_x_at 207245_at 203951_at 216401_x_at 207390_s_at203980_at 216442_x_at 207392_x_at 204069_at 216474_x_at 207432_at204083_s_at 216576_x_at 207761_s_at 204122_at 216834_at 208596_s_at204135_at 216984_x_at 208920_at 204326_x_at 217148_x_at 209114_at204438_at 217179_x_at 209374_s_at 204457_s_at 217235_x_at 209458_x_at204570_at 217258_x_at 209791_at 204688_at 217378_x_at 210107_at204697_s_at 217480_x_at 210524_x_at 204719_at 217546_at 210735_s_at204745_x_at 217757_at 211372_s_at 204834_at 217762_s_at 211538_s_at204894_s_at 217764_s_at 211549_s_at 204931_at 217767_at 211637_x_at204938_s_at 217897_at 211699_x_at 204939_s_at 217967_s_at 211745_x_at204940_at 218087_s_at 212224_at 204955_at 218162_at 212592_at 205097_at218224_at 212741_at 205200_at 218312_s_at 212814_at 205267_at 218353_at213317_at 205382_s_at 218418_s_at 213451_x_at 205412_at 218468_s_at213629_x_at 205433_at 218469_at 213921_at 205464_at 218559_s_at213953_at 205547_s_at 218756_s_at 214164_x_at 205683_x_at 219014_at214433_s_at 205935_at 219087_at 214598_at 205950_s_at 219508_at214916_x_at 206134_at 219607_s_at 215125_s_at 206143_at 219669_at215299_x_at 206149_at 219799_s_at 215867_x_at 206198_s_at 220026_at216336_x_at 206199_at 220037_s_at 216491_x_at 206208_at 220376_at216510_x_at 206209_s_at 220834_at 217022_s_at 206422_at 221541_at217109_at 206461_x_at 221667_s_at 217110_s_at 206561_s_at 221747_at217165_x_at 206576_s_at 221748_s_at 217232_x_at 206637_at 222043_at217414_x_at 206641_at 222162_s_at 218541_s_at 206710_s_at 222453_at218546_at 206784_at 222513_s_at 219059_s_at 207003_at 222717_at219543_at 207080_s_at 222722_at 219796_s_at 207134_x_at 223121_s_at219948_x_at 207266_x_at 223122_s_at 220075_s_at 207502_at 223235_s_at220266_s_at 207961_x_at 223343_at 220468_at 207977_s_at 223395_at220645_at 207980_s_at 223551_at 220812_s_at 208131_s_at 223623_at221004_s_at 208370_s_at 223952_x_at 221305_s_at 208383_s_at 224009_x_at221584_s_at 208399_s_at 224352_s_at 221841_s_at 208450_at 224412_s_at221896_s_at 208581_x_at 224480_s_at 223484_at 208747_s_at 224560_at223597_at 208763_s_at 224663_s_at 223754_at 208788_at 224694_at224342_x_at 208789_at 224823_at 224989_at 208791_at 224836_at 224990_at208792_s_at 224840_at 225458_at 208894_at 224959_at 225728_at 209047_at224963_at 226147_s_at 209074_s_at 224964_s_at 226302_at 209101_at225207_at 226594_at 209116_x_at 225242_s_at 226654_at 209138_x_at225269_s_at 226811_at 209147_s_at 225275_at 227052_at 209156_s_at225353_s_at 227522_at 209167_at 225381_at 227682_at 209170_s_at225442_at 227725_at 209191_at 225575_at 227735_s_at 209209_s_at225602_at 227736_at 209210_s_at 225604_s_at 228133_s_at 209283_at225626_at 228195_at 209301_at 225688_s_at 228232_s_at 209312_x_at225710_at 228241_at 209335_at 225720_at 228469_at 209357_at 225721_at228961_at 209373_at 225782_at 229070_at 209436_at 225894_at 229254_at209457_at 225895_at 229659_s_at 209496_at 226001_at 229831_at 209498_at226051_at 230595_at 209612_s_at 226084_at 231925_at 209613_s_at226103_at 231975_s_at 209621_s_at 226303_at 233565_s_at 209651_at226304_at 235146_at 209656_s_at 226333_at 235766_x_at 209667_at226430_at 235849_at 209668_x_at 226492_at 238143_at 209687_at 226682_at238750_at 209735_at 226694_at 238751_at 209763_at 226818_at 239272_at209868_s_at 226834_at 241994_at 209948_at 226841_at 242447_at210084_x_at 227006_at 242601_at 227099_s_at 227061_at 243278_at; and/or

CLCA4 SGK MT1X ZG16 CFL2 AOC3 CA2 C1S PPAP2A CA1 SELENBP1 ZSCAN18 MS4A12MT1E IVD AQP8 ADAMTS1 SFRP1 SLC4A4 ITM2A COL4A2 CEACAM7 POU2AF1 GPM6BTAGLN FAM55D EPB41L3 GUCA1B C6orf204 MAOA GCG AKAP12 DMD ADH1B TUBB6MSRB3 UGT2B17 LGALS2 PLOD2 ADAMDEC1 KIAA0828 C9orf19 MT1M MGC14376 MIER3AKR1B10 PPP1R14A XDH FNI MUC4 CLDN23 MGP PKIB SGCE CXCL12 PIGR FOXF2PDK4 ASPN AGR3 CA4 A2M IGLJ3 PYY LOC25845 QKI IGHA1 LGALS1 LOC399959TPM2 BCHE ANKRD25 C6orf105 ST6GALNAC1 CRISPLD2 HPGD GJA1 ANK2 ADH1CSCNN1B LOC283666 CLCA1 FABP4 CRYAB FABP1 F13A1 ACAT1 ENAM CD36 IGL@ CFDSPARCL1 PBLD GUCA2B ZCWPW2 CCL8 FBLN1 TNC LIFR LOC63928 MT1A HLA-DRB1ABCA8 LOC652745 UGP2 POSTN MALL IGKV1D-13 DCN GNG2 AP1S2 ITLN1 DNASE1L3EMP3 COL6A2 EGR1 MMP28 FCGBP CMBL UGT2A3 SLC26A2 GCNT3 RGS5 PGM5SERPING1 PTGIS DMN MEIS1 DUSP5 GPNMB EDN3 MFAP4 IGFBP5 MSN UGT1A6 CLEC3BMT1G PRKAR2B LOC253012 TPSAB1 HHLA2 DPT GPX3 LOC652128 PCK1 CDKN2B C3CNN1 FOSB ATP2B4 HSD17B2 HSPA1A HBA1 PLAC8 CYBRD1 TCF21 TMEM47 PTGER4PPID OGN MAG1 PPAP2B CALD1 BEST2 SPON1 ACTG2 HLA-DQA1 PHLDB2 MGC4172PRIMA1 RARRES2 MAB21L2 MT1F ETHE1 RPL24 MAFB MMP2 ABCG2 FAM107A SRICCDC80 PRKACB CNTN3 UGT1A1 SELM RGS2 MRC1 TYROBP COL6A1 HSD11B2 TNS1FBN1 ANPEP MYH11 MXD1 MATN2 ITM2C PLCE1 PRNP CES2 KCNMB1 ABI3BP MS4A4ACALM1 HLA-C PDGFRA HLA-DPB1 NDE1 CA12 SMOC2 SRPX FKBP5 LOC285382 WWTR1HSPB8 CLIC5 HMGCS2 TPSB2 APOE LOC646627 FGL2 SERPINF1 KRT20 C1QBPPP1R12B KLF4 ANGPTL1 HSPB6 FHL1 MEP1A FNBP1 ARL14 GUCY1A3 C4orf34 LUMUGDH SORBS2 SORBS1 DUSP1 GPA33 METTL7A C2orf40 GALNAC4S-6ST FAM129A PLNCFHR1 SCARA5 UGT2B15 MGC13057 SI PDLIM3 C10orf56 ACTA2 TP53INP2 SULT1A1CD177 ATP8B1 TTRAP C10orf99 ANK3 CCL28 COL15A1 CTGF IDH3A NR3C2 MUCDHLEDG2 DHRS9 SDPR UGT1A8 LMOD1 COL14A1 RAB27A EFEMP1 DSCR1 ANTXR1 GREM1CITED2 EMP1 IL1R2 MT1H CSRP1 LOC387763 NEXN PLEKHC1 TIMP3 MUC2 LOC572558MYLK NID1 FOXP2 CLDN8 HBB HSPA2 RDX GCNT2 ATP1A2 TSPAN7 C20orf118 TNXBTNFRSF17 SLC20A1 FUCA1 SYNPO2 CD14 MRGPRF VIM KCTD12 HIGD1A SMPDL3ARBMS1 MFSD4 P2RY14 PTRF AXL CHGA TSPAN1 AQP1 C15orf48 UGT1A9 MAP1BCOL3A1 COX7A1 PALLD CYR61 MUC12 MPEG1 TRPM6 PDCD4 KLHL5 OSTbeta CAV1TCEAL7 IGLV1-44 FAM46C FILIPIL VSIG2 LRIG1 IQGAP2 IGHM HLA-DPA1 PRDX6LRRC19 C1orf115 RAB31 CD163 HBA2 LOC96610 CEACAM1 EDIL3 FGFR2 TIMP2 DESPAPSS2 ENTPD5 MT2A XLKD1 DDR2 KCNMA1 SMTN CHRDL1 GAS1 C8orf4 SRGN TBC1D9SDCBP2 PDE9A C7 CCL11 PMP22 P2RY1 ELOVL5 FLNA NR3C1 FOXF1 STMN2 STOMRELLI MYL9 CKB PNMA1 SEMA6D CLU LOC339562 PADI2 SLC26A3 PALM2-AKAP2SEPP1 SDC2 PAG1 TGFB1I1 SST HCLS1 SFRP2 HLA-DRA RGS1 UGT1A3 TSC22D3FXYD6 MS4A7 IL6ST OLFML3 ALDH1A1 C1QC COL6A3in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state.

Another aspect of the present invention provides a method of screeningfor the onset or predisposition to the onset of a large intestineneoplasm in an individual, said method comprising assessing the level ofexpression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 220026_at; and/or    -   (ii) CLCA4        in a biological sample from said individual wherein a lower        level of expression of the gene or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

In yet another aspect there is provided a method of screening for theonset or predisposition to the onset of a large intestine neoplasm in anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 214142_at; and/or    -   (ii) ZG16        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

In still another aspect there is provided a method of screening for theonset or predisposition to the onset of a large intestine neoplasm in anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

209301_at 205950_s_at; and/or

-   -   (ii)

CA2 CA1in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state.

In still yet another aspect there is provided a method of screening forthe onset or predisposition to the onset of a large intestine neoplasmin an individual, said method comprising assessing the level ofexpression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 220834_at; and/or    -   (ii) MS4A12        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

In yet still another aspect there is provided a method of screening forthe onset or predisposition to the onset of a large intestine neoplasmin an individual, said method comprising assessing the level ofexpression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 206784_at; and/or    -   (ii) AQP8        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

In a further aspect there is provided a method of screening for theonset or predisposition to the onset of a large intestine neoplasm in anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   the gene, genes or transcripts detected by Affymetrix probeset        IDs: 203908_at, 206198_s_at, 205547_s_at, 207003_at, 206422_at,        209613_s_at, 207245_at; and/or    -   (ii) SLC4A4, CEACAM7, TAGLN, GUCA1B, GCG, ADH1B, UGT2B17,        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

In another further aspect there is provided a method of screening forthe onset or predisposition to the onset of a large intestine neoplasmin an individual, said method comprising assessing the level ofexpression of one or more genes or transcripts selected from:

-   -   the gene, genes or transcripts detected by Affymetrix probeset        IDs: 203908_at, 206198_s_at, 205547_s_at, 207003_at, 206422_at,        209613_s_at, 207245_at; and/or    -   (ii) SLC4A4, CEACAM7, TAGLN, GUCA1B, GCG, ADH1B, UGT2B17,        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

In still another further aspect there is provided a method of screeningfor the onset or predisposition to the onset of a large intestineneoplasm in an individual, said method comprising screening the level ofexpression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

225207_at 211548_s_at 205382_s_at 206208_at 206262_at 207502_at207080_s_at 210107_at 202995_s_at 215118_s_at 205892_s_at 206149_at_204083_s_at 212592_at 204719_at 229070_at; and/or

-   -   (ii)

PDK4 HPGD CFD CA4 ADH1C GUCA2B PYY CLCA1 FBLN1 IGHA1 FABP1 LOC63928 TPM2ENAM ABCA8 C6orf105in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state.

In yet still yet another further aspect there is provided a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising screeningthe level of expression of one or more genes or transcripts selectedfrom:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

210809_s_at 201617_x_at 202133_at 201893_x_at 202274_at 204607_at223597_at 218756_s_at 238143_at 209156_s_at 210302_s_at 213953_at203240_at 228885_at 220266_s_at 224963_at 209735_at 210299_s_at226303_at 228504_at 220468_at 212730_at 225242_s_at 201744_s_at201141_at 215125_s_at 218087_s_at 211959_at 204438_at 207761_s_at205200_at 204130_at 217967_s_at 242601_at 202888_s_at 229839_at213068_at 202350_s_at 206664_at 208383_s_at 201300_s_at 200974_at203951_at 223395_at 219669_at 204818_at 214768_x_at 227736_at 219014_at228133_s_at 203477_at 209656_s_at 204955_at 205259_at 222722_at; and/or

-   -   (ii)

POSTN OGN WWTR1 DCN CALD1 HMGCS2 ITLN1 ACTG2 LOC646627 COL6A2 MGC4172KRT20 FCGBP MAB21L2 KLF4 SLC26A2 RPL24 FHL1 PGM5 ABCG2 ARL14 DMN CCDC80LUM GPNMB UGT1A1 SORBS1 IGFBP5 MRC1 METTL7A CLEC3B HSD11B2 FAM129ALOC253012 ANPEP SCARA5 DPT MATN2 SI PCK1 PRNP ACTA2 CNN1 ABI3BP CD177HSD17B2 HLA-C C10orf99 PLAC8 NDE1 COL15A1 TMEM47 SRPX NR3C2in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state.

In a related aspect the present invention is directed to a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising screeningthe level of expression of one or more genes or transcripts selectedfrom:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

200600_at 208788_at 215382_x_at 200665_s_at 208789_at 215388_s_at200799_at 208894_at 216442_x_at 200845_s_at 209047_at 216474_x_at200859_x_at 209101_at 216834_at 200897_s_at 209138_x_at 217480_x_at200974_at 209147_s_at 217757_at 200986_at 209156_s_at 217762_s_at201041_s_at 209191_at 217764_s_at 201061_s_at 209209_s_at 217767_at201069_at 209210_s_at 217897_at 201105_at 209312_x_at 218162_at201137_s_at 209335_at 218224_at 201141_at 209436_at 218312_s_at201150_s_at 209457_at 218353_at 201289_at 209496_at 218418_s_at201300_s_at 209621_s_at 218468_s_at 201426_s_at 209651_at 218469_at201438_at 209656_s_at 218559_s_at 201616_s_at 209868_s_at 219087_at201617_x_at 210084_x_at 219607_s_at 201645_at 210133_at 221541_at201667_at 210139_s_at 222043_at 201743_at 210495_x_at_ 222453_at201744_s_at 210517_s_at 222513_s_at 201842_s_at 210764_s_at 223121_s_at201852_x_at 210809_s_at 223122_s_at 201858_s_at 210982_s_at 223235_s_at201859_at 211161_s_at_ 223343_at 201865_x_at 211596_s_at 224560_at201893_x_at 211671_s_at 224694_at 201920_at 211719_x_at 224840_at202007_at 211813_x_at 224964_s_at 202069_s_at 211896_s_at 225242_s_at202133_at 211959_at 225269_s_at 202283_at 211964_at 225353_s_at202291_s_at 211985_s_at 225381_at 202403_s_at 211990_at 225442_at202620_s_at 211991_s_at 225602_at 202686_s_at 212077_at 225604_s_at202760_s_at 212091_s_at 225626_at 202766_s_at 212136_at 225688_s_at202953_at 212158_at 225710_at 202957_at 212185_x_at 226001_at202994_s_at 212195_at 226051_at 202995_s_at 212230_at 226084_at203066_at 212233_at 226103_at 203131_at 212265_at 226430_at 203305_at212386_at 226682_at 203382_s_at 212387_at 226694_at 203477_at 212397_at226818_at 203645_s_at 212414_s_at 226834_at 203680_at 212419_at226841_at 203729_at 212464_s_at 227061_at 203748_x_at 212667_at227099_s_at 204069_at 212671_s_at 227235_at 204122_at 212713_at227404_s_at 204135_at 212764_at 227529_s_at 204438_at 212956_at227561_at 204457_s_at 213428_s_at 227623_at 204570_at 213509_x_at227705_at 204688_at 213746_s_at 227727_at 205412_at 213891_s_at228507_at 205683_x_at 214038_at 228750_at 205935_at 214677_x_at228846_at 207134_x_at 214752_x_at 229530_at 207266_x_at 215049_x_at230264_s_at 208131_s_at 215076_s_at 231579_s_at 208370_s_at 215193_x_at234987_at; and/or 208747_s_at

-   -   (ii)

A2M FBN1 PALLD ACAT1 FILIP1L PALM2-AKAP2 ACTA2 FKBP5 PDGFRA AKAP12 FLNAPDLIM3 ANKRD25 FN1 PHLDB2 ANTXR1 FOXF1 PLEKHC1 AP1S2 FXYD6 PLOD2 APOEGALNAC4S-6ST PMP22 AQP1 GAS1 PNMA1 ASPN GJA1 POSTN ATP2B4 GNG2 PPAP2AAXL GPNMB PPAP2B C10orf56 GREM1 PRDX6 C1QB GUCY1A3 PRKAR2B C1QC HCLS1PRNP C1S HLA-DPA1 PTGIS C20orf118 HLA-DPB1 PTRF C3 HLA-DQA1 QKI C9orf19HLA-DRA RAB31 CALD1 HLA-DRB1 RARRES2 CALM1 HSPA1A RBMS1 CCDC80 IDH3A RDXCCL11 IGFBP5 RELL1 CCL8 IGL@ RGS1 CD14 IGLJ3 RGS5 CD163 IL6ST SDC2 CES2KLHL5 SELM CFHR1 LGALS1 SEPT6 CLU LOC283666 SERPINF1 COL14A1 LOC339562SERPING1 COL15A1 LOC387763 SFRP2 COL1A2 LOC399959 SGCE COL3A1 LRIG1SLC20A1 COL4A2 LUM SMOC2 COL6A1 MAFB SORBS1 COL6A2 MAP1B SPARC COL6A3MEIS1 SPON1 COX7A1 MFAP4 SRGN CRISPLD2 MGP STOM CTGF MMP2 TBC1D9 CYBRD1MPEG1 TCEAL7 CYR61 MRC1 TGFB1I1 DCN MRGPRF TIMP2 DDR2 MS4A4A TIMP3 DSCR1MS4A7 TMEM47 DUSP1 MSN TNC DUSP5 MT2A TPSAB1 EFEMP1 MXD1 TPSB2 EGR1 NEXNTUBB6 ELOVL5 NID1 TYROBP EMP3 NR3C1 VIM F13A1 OLFML3 WWTR1 FBLN1 PAG1ZSCAN18in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of an adenoma cell or a cellpredisposed to the onset of an adenoma state.

In another aspect of the present invention there is provided a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising screeningthe level of expression of one or more genes or transcripts selectedfrom:

-   -   (i) the gene or genes detected by Affymetrix probeset IDs:

200884_at 208596_s_at 220812_s_at 201495_x_at 208920_at 221004_s_at202266_at 209114_at 221305_s_at 202350_s_at 209374_s_at 221584_s_at202731_at 209458_x_at 221841_s_at 202741_at 209791_at 221896_s_at202742_s_at 210107_at 223484_at 202768_at 210524_x_at 223597_at202838_at 210735_s_at 223754_at 203058_s_at 211372_s_at 224342_x_at203060_s_at 211538_s_at 224989_at 203240_at 211549_s_at 224990_at203296_s_at 211637_x_at 225458_at 203343_at 211699_x_at 225728_at203474_at 211745_x_at 226147_s_at 203638_s_at 212224_at 226302_at203963_at 212592_at 226594_at 204018_x_at 212741_at 226654_at 204034_at212814_at 226811_at 204036_at 213317_at 227052_at 204130_at 213451_x_at227522_at 204388_s_at 213629_x_at 227682_at 204389_at 213921_at227725_at 204508_s_at 213953_at 227735_s_at 204532_x_at 214164_x_at227736_at 204607_at 214433_s_at 228133_s_at 204673_at 214598_at228195_at 204818_at 214916_x_at 228232_s_at 204895_x_at 215125_s_at228241_at 204897_at 215299_x_at 228469_at 205112_at 215867_x_at228961_at 205259_at 216336_x_at 229070_at 205403_at 216491_x_at229254_at 205480_s_at 216510_x_at 229659_s_at 205554_s_at 217022_s_at229831_at 205593_s_at 217109_at 230595_at 205892_s_at 217110_s_at231925_at 205929_at 217165_x_at 231975_s_at 206000_at 217232_x_at233565_s_at 206094_x_at 217414_x_at 235146_at 206262_at 218541_s_at235766_x_at 206377_at 218546_at 235849_at 206385_s_at 219059_s_at238143_at 206664_at 219543_at 238750_at 207126_x_at 219796_s_at238751_at 207245_at 219948_x_at 239272_at 207390_s_at 220075_s_at241994_at 207392_x_at 220266_s_at 242447_at 207432_at 220468_at242601_at 207761_s_at 220645_at 243278_at; and/or

-   -   (ii)

ADH1C HIGD1A NR3C2 AGR3 HMGCS2 P2RY1 ALDH1A1 HPGD PADI2 ANK3 HSD11B2PAPSS2 ARL14 HSD17B2 PBLD ATP1A2 HSPA2 PDCD4 ATP8B1 IGHA1 PDE9A BEST2IGHM PIGR C10orf99 IL1R2 PLCE1 C15orf48 IL8 PPID C1orf115 IQGAP2 PRKACBC4orf34 ITLN1 PTGER4 C6orf105 ITM2C RAB27A C8orf4 KCNMA1 SCARA5 CA12KIAA0828 SDCBP2 CCL28 KLF4 SELENBP1 CKB KRT20 SI CLCA1 LOC253012 SMTNCLDN8 LOC25845 SORBS2 CLIC5 LOC285382 SRI CMBL LOC572558 SST CNTN3LOC646627 ST6GALNAC1 DNASE1L3 LOC652128 SULT1A1 EDG2 LOC96610 TNXB ENAMMAOA TSPAN1 ENTPD5 MATN2 TTRAP ETHE1 MEP1A UGDH FABP1 METTL7A UGP2FAM46C MFSD4 UGT1A1 FAM55D MGC13057 UGT1A3 FCGBP MIER3 UGT1A6 FGFR2MMP28 UGT1A8 FOSB MT1A UGT1A9 FOXF2 MT1F UGT2A3 FOXP2 MT1M UGT2B15 FUCA1MUC12 UGT2B17 GPA33 MUC2 VSIG2 HBA1 MUC4 XDH HBA2 MUCDHL XLKD1 HBB MYH11ZCWPW2 HHLA2 NDE1in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a cancer cell or a cellpredisposed to the onset of a cancerous state.

In still another aspect there is provided a method of screening for theonset or predisposition to the onset of a large intestine neoplasm in anindividual, said method comprising screening the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

202920_at 222717_at 231120_x_at 203881_s_at 224412_s_at 231773_at204719_at 225381_at 203296_s_at 204931_at 225575_at 206664_at 204940_at227529_s_at 211549_s_at 205433_at 227623_at 214598_at 206637_at227705_at 219948_x_at 207080_s_at 227827_at 220812_s_at 207980_s_at228504_at 221305_s_at 209170_s_at 228706_s_at 229831_at 209209_s_at228766_at 231925_at 209613_s_at 228854_at 235146_at 220037_s_at228885_at 238751_at 220376_at 230788_at 243278_at; and/or

-   -   (ii)

ADH1B ANGPTL1 HHLA2 SORBS2 DMD SORBS2 PYY GCNT2 CLDN23 ABCA8 SDPR CNTN3RPL24 PKIB PLEKHC1 SI CITED2 LRRC19 CLDN8 TCF21 LIFR P2RY14 P2RY1 ATP1A2PLN ANK2 HPGD TRPM6 XLKD1 GPM6B CD36 LOC399959 UGT1A8 BCHE AKAP12 FOXP2TCEAL7 UGT2A3in a biological sample from said individual wherein a level ofexpression of the genes or transcripts of group (i) and/or group (ii)which is not substantially above background levels is indicative of aneoplastic cell or a cell predisposed to the onset of a neoplasticstate.

In a further aspect there is provided a method of screening for theonset or predisposition to the onset of a large intestine neoplasm in anindividual, said method comprising screening the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 209209_s_at, 225381_at, 227529_s_at, 227623_at,        227705_at; and/or    -   (ii) AKAP12, LOC399959, PLEKHC1, TCEAL7,        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) which is not substantially above background        levels is indicative of an adenoma cell or a cell predisposed to        the onset of an adenoma state.

In yet still another further aspect there is provided a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising screeningthe level of expression of one or more genes or transcripts selectedfrom:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

203296_s_at 219948_x_at 231925_at 206664_at 220812_s_at 235146_at211549_s_at 221305_s_at 238751_at 214598_at 229831_at 243278_at; and/or

-   -   (ii)

ATP1A2 HHLA2 SORBS2 CLDN8 HPGD UGT1A8 CNTN3 P2RY1 UGT2A3 FOXP2 SIin a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)which is not substantially above background levels is indicative of acancer cell or a cell predisposed to the onset of a cancerous state.

In another further aspect there is provided a method of characterising aneoplastic cell or cellular population, which cell or cellularpopulation is derived from the large intestine of an individual, saidmethod comprising assessing the level of expression of one or more genesor transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

200600_at 204006_s_at 213428_ s_at 200665_s_at 204051_s_at 213524_ s_at200832_s_at 204122_at 213869_x_at 200974_at 204320_at 213905_x_at200986_at 204475_at 214247_s_at 201058_s_at 204620_s_at 215049_x_at201069_at 205479_s_at 215076_s_at 201105_at 205547_s_at 215646_s_at201141_at 205828_at 216442_x_at 201147_s_at 207173_x_at 217430_x_at201150_s_at 207191_s_at 217762_s_at 201162_at 208747_s_at 217763_s_at201163_s_at 208782_at 217764_s_at 201185_at 208788_at 218468_s_at201261_x_at 208850_s_at 218469_at 201289_at 208851_s_at 218559_s_at201426_s_at 209101_at 218638_s_at 201438_at 209156_s_at 219087_at201616_s_at 209218_at 221011_s_at 201645_at 209395_at 221729_at201667_at 209396_s_at 221730_at 201744_s_at 209596_at 221731_x_at201792_at 209875_s_at 37892_at 201842_s_at 209955_s_at 223122_s_at201852_x_at 210095_s_at 223235_s_at 201859_at 210495_x_at 224560_at201893_x_at 210511_s_at 224694_at 202237_at 210764_s_at 224724_at202238_s_at 210809_s_at 225664_at 202283_at 211161_s_at 225681_at202291_s_at 211571_s_at 225710_at 202310_s_at 211719_x_at 225799_at202311_s_at 211813_x_at 226237_at 202403_s_at 211896_s_at 226311_at202404_s_at 211959_at 226694_at 202450_s_at 211964_at 226777_at202620_s_at 211966_at 226930_at 202766_s_at 211980_at 227099_s_at202859_x_at 211981_at 227140_at 202878_s_at 212077_at 227566_at202917_s_at 212344_at 229218_at 202998_s_at 212353_at 229802_at203083_at 212354_at 231579_s_at 203325_s_at 212464_s_at 231766_s_at203382_s_at 212488_at 231879_at 203477_at 212489_at 232458_at 203570_at212667_at 233555_s_at 203645_s_at 213125_at 234994_at; and/or203878_s_at

-   -   (ii)

COL1A2 LGALS1 SRGN CTHRC1 ELOVL5 LBH FN1 MGP CTGF POSTN MMP2 TNC SPP1LOXL2 G0S2 MMP1 MYL9 SQLE SPARC DCN EFEMP1 LUM CALD1 APOE GREM1 FBN1 MSNIL8 MMP3 IGFBP3 IGFBP5 IGFBP7 SERPINF1 SFRP2 FSTL1 ISLR SULF1 COL4A2 HNTASPN VCAN COL5A1 COL6A3 SMOC2 OLFML2B COL8A1 HTRA1 KIAA1913 COL12A1CYR61 PALM2-AKAP2 COL5A2 FAP SERPING1 CDH11 VIM TYROBP THBS2 TIMP2 ACTA2COL15A1 SCD COL3A1 COL11A1 TIMP3 PLOD2 S100A8 AEBP1 MMP11 FNDC1 GJA1CD163 SFRP4 NNMT FCGR3B INHBA COL1A1 PLAU COL6A2 SULF2 MAFB ANTXR1COL6A1 LOC541471 GPNMB SPON2 LOC387763 BGN CTSK CHI3L1 TAGLN MXRA5 THY1COL4A1 C1S LOXL1 RAB31 DKK3 CD93in said cell or cellular population wherein a lower level of expressionof the genes of group (i) and/or group (ii) relative to agastrointestinal cancer control level is indicative of an adenoma cellor a cell predisposed to the onset of an adenoma state.

In still another aspect there is provided a method of characterising aneoplastic cell or cellular population, which cell or cellularpopulation is derived from the large intestine of an individual, saidmethod comprising assessing the level of expression of one or more genesor transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

200884_at 214234_s_at 226248_s_at 203240_at 214235_at 226302_at203963_at 214433_s_at 227676_at 204508_s_at 215125_s_at 227719_at204607_at 215867_x_at 227725_at 204811_s_at 217109_at 228232_s_at204895_x_at 217110_s_at 229070_at 204897_at 218211_s_at 231832_at205259_at 219543_at 232176_at 205765_at 219955_at 232481_s_at205927_s_at 221841_s_at 235976_at 208063_s_at 221874_at 236894_at208937_s_at 223969_s_at 237521_x_at 210107_at 223970_at 242601_at;and/or 213106_at

-   -   (ii)

CLCA1 CTSE ATP8B1 FCGBP C6orf105 CACNA2D2 HMGCS2 CKB KLF4 RETNLB ATP8A1CYP3A5P2 L1TD1 MUC4 CAPN9 SLITRK6 UGT1A1 NR3C2 VSIG2 SELENBP1 PBLDLOC253012 PTGER4 CA12 ST6GALNAC1 MLPH WDR51B ID1 KIAA1324 FAM3D CYP3A5in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to a gastrointestinal adenoma control level is indicative of acancer or a cell predisposed to the onset of a cancerous state.

In yet another aspect there is provided a method of characterising aneoplastic cell or cellular population, which cell or cellularpopulation is derived from the large intestine of an individual, saidmethod comprising assessing the level of expression of one or more genesor transcripts selected from:

-   -   (i) the gene or genes detected by Affymetrix probeset IDs:        202404_s_at, 212464_s_at, 210809_s_at, 225681_at; and/or    -   (ii) COL1A2, FN1, POSTN, CTHRC1        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to a gastrointestinal cancer control        level is indicative of an adenoma cell or a cell predisposed to        the onset of an adenoma state.

In yet still another aspect, there is provided a method ofcharacterising a neoplastic cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising assessing the level of expression ofone or more genes selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

209875_s_at 227140_at 204475_at; and/or

-   -   (ii)

SPP1 MMP1in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to a gastrointestinal cancer control level is indicative of anadenoma cell or a cell predisposed to the onset of an adenoma state.

In still yet another aspect the present invention is directed to amethod of characterising a cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

200665_s_at 226237_at 226930_at 201744_s_at 225664_at 204051_s_at218468_s_at 221730_at 210511_s_at 202859_x_at 207173_x_at 209156_s_at211959_at 203083_at 224694_at 223122_s_at 203477_at 201141_at 212353_at37892_at 213905_x_at 219087_at 202917_s_at 205547_s_at 201438_at; and/or

-   -   (ii)

SPARC COL8A1 SFRP4 LUM COL12A1 INHBA GREM1 COL5A2 COL6A2 IL8 CDH11ANTXR1 IGFBP5 THBS2 GPNMB SFRP2 COL15A1 BGN SULF1 COL11A1 TAGLN ASPNS100A8 COL6A3 FNDC1in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or (ii) relativeto a gastrointestinal cancer control level is indicative of an adenomaor a cell predisposed to the onset of an adenoma state.

In yet another aspect the present invention is directed to a method ofcharacterising a cell or cellular population, which cell or cellularpopulation is derived from the large intestine of an individual, saidmethod comprising assessing the level of expression of one or more genesor transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 210107_at; and/or    -   (ii) CLCA1        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or (ii) relative to a gastrointestinal adenoma control level        is indicative of a cancer or a cell predisposed to the onset of        a cancerous state.

In still yet another aspect the present invention is directed to amethod of characterising a cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

203240_at 219955_at 242601_at 204607_at 232481_s_at 227725_at223969_s_at 228232_s_at; and/or

-   -   (ii)

FCGBP L1TD1 LOC253012 HMGCS2 SLITRK6 ST6GALNAC1 RETNLB VSIG2in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or (ii) relativeto a gastrointestinal adenoma control level is indicative of a cancer ora cell predisposed to the onset of a cancerous state.

A further aspect of the present invention provides a method ofcharacterising a neoplastic cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene or genes detected by Affymetrix probeset IDs:

235976_at 236894_at 237521; and/or

-   -   (ii)

SLITRK6 L1TD1in a biological sample from said individual wherein expression of thegenes or transcripts of group (i) and/or (ii) at a level which is notsubstantially greater than background neoplastic tissue levels isindicative of a cancer or a cell predisposed to the onset of a cancerousstate.

A related aspect of the present invention provides a molecular array,which array comprises a plurality of:

-   (i) nucleic acid molecules comprising a nucleotide sequence    corresponding to any one or more of the neoplastic marker genes    hereinbefore described or a sequence exhibiting at least 80%    identity thereto or a functional derivative, fragment, variant or    homologue of said nucleic acid molecule; or-   (ii) nucleic acid molecules comprising a nucleotide sequence capable    of hybridising to any one or more of the sequences of (i) under    medium stringency conditions or a functional derivative, fragment,    variant or homologue of said nucleic acid molecule; or-   (iii) nucleic acid probes or oligonucleotides comprising a    nucleotide sequence capable of hybridising to any one or more of the    sequences of (i) under medium stringency conditions or a functional    derivative, fragment, variant or homologue of said nucleic acid    molecule; or-   (iv) probes capable of binding to any one or more of the proteins    encoded by the nucleic acid molecules of (i) or a derivative,    fragment or, homologue thereof    wherein the level of expression of said marker genes of (i) or    proteins of (iv) is indicative of the neoplastic state of a cell or    cellular subpopulation derived from the large intestine.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphical representation of alcohol dehydrogenase IB (classI), beta polypeptide.

FIG. 2 is a graphical representation of the methylation of MAMDC2 andGPM6B in normal and neoplastic tissues and cell lines. Panel A shows themethylation level of the MAMDC2 gene as assessed by methylation specificPCR, using amplification of the CAGE gene to normalise for input DNAlevels. Each point represents an individual tissue sample or cell line.Samples included DNAs from 18 colorectal cancer tissues, 12 colorectaladenomas, 22 matched normal colorectal tissues, 6 other normal tissuesand a cell line and 6 colon cancer cell lines. Panel B shows therelative level of methylation of the GPM6B gene assessed by a COBRAassay. Levels of methylation were scored between 0 (no restrictionenzyme digestion) and 5 (complete restriction enzyme digestion). Eachpoint represents a single tissue sample. Samples included 14 colorectalcancer tissues, 11 colorectal adenomas and 22 matched normal tissues.

FIG. 3 is a schematic representation of predicted RNA variants derivedfrom hCG_(—)1815491. cDNA clones derived from map region 8579310 to8562303 on human chromosome 16 were used to locate exon sequences.Arrows: Oligo nucleotide primer sets were designed to allow measurementof individual RNA variants by PCR. Primers covering splice junctions areshown as spanning intron sequences which is not included in the actualoligonucleotide primer sequence.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is predicated, in part, on the elucidation of geneexpression profiles which characterise large intestine cellularpopulations in terms of their neoplastic state and, more particularly,whether they are malignant or pre-malignant. This finding has nowfacilitated the development of routine means of screening for the onsetor predisposition to the onset of a large intestine neoplasm orcharacterising cellular populations derived from the large intestinebased on screening for downregulation of the expression of thesemolecules, relative to control expression patterns and levels. To thisend, in addition to assessing expression levels of the subject genesrelative to normal or non-neoplastic levels, it has been determined thata proportion of these genes are not expressed in the diseased state,thereby facilitating the development of a simple qualitative test basedon requiring assessment only relative to test background levels.

In accordance with the present invention, it has been determined thatthe genes detailed above are modulated, in terms of differential changesto their levels of expression, depending on whether the cell expressingthat gene is neoplastic or not. It should be understood that referenceto a gene “expression product” or “expression of a gene” is a referenceto either a transcription product (such as primary RNA or mRNA) or atranslation product such as protein. In this regard, one can assesschanges to the level of expression of a gene either by screening forchanges to the level of expression product which is produced (i.e. RNAor protein), changes to the chromatin proteins with which the gene isassociated, for example the presence of histone H3 methylated on lysineat amino acid position number 9 or 27 (repressive modifications) orchanges to the DNA itself which acts to downregulate expression, such aschanges to the methylation of the DNA. These genes and their geneexpression products, whether they be RNA transcripts, changes to the DNAwhich act to downregulate expression or encoded proteins, arecollectively referred to as “neoplastic markers”.

Accordingly, one aspect of the present invention is directed to a methodof screening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising assessingthe level of expression of one or more genes or transcripts selectedfrom:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

200600_at 210133_at 227235_at 200621_at 210139_s_at 227265_at 200795_at210298_x_at 227404_s_at 200799_at 210299_s_at 227529_s_at 200845_s_at210302_s_at 227561_at 200859_x_at 210495_x_at 227623_at 200897_s_at210517_s_at 227662_at 200974_at 210764_s_at 227705_at 200986_at210809_s_at 227727_at 201041_s_at 210946_at 227826_s_at 201058_s_at210982_s_at 227827_at 201061_s_at 211161_s_at 228202_at 201069_at211548_s_at 228504_at 201105_at 211596_s_at 228507_at 201137_s_at211643_x_at 228640_at 201141_at 211644_x_at 228706_s_at 201150_s_at211645_x_at 228707_at 201289_at 211671_s_at 228750_at 201300_s_at211696_x_at 228766_at 201324_at 211719_x_at 228846_at 201348_at211798_x_at 228854_at 201426_s_at 211813_x_at 228885_at 201427_s_at211848_s_at 229530_at 201438_at 211889_x_at 229839_at 201496_x_at211896_s_at 230087_at 201497_x_at 211959_at 230264_s_at 201539_s_at211964_at 230788_at 201540_at 211985_s_at 230830_at 201616_s_at211990_at 231120_x_at 201617_x_at 211991_s_at 231579_s_at 201645_at212077_at 231773_at 201667_at 212091_s_at 234764_x_at 201739_at212097_at 234987_at 201743_at 212136_at 236300_at 201744_s_at 212158_at236313_at 201842_s_at 212185_x_at 242317_at 201852_x_at 212192_at200884_at 201858_s_at 212195_at 201495_x_at 201859_at 212230_ at202266_at 201865_x_at 212233_at 202350_s_at 201893_x_at 212265_at202731_at 201920_at 212288_at 202741_at 201957_at 212386_at 202742_s_at202007_at 212387_at 202768_at 202037_s_at 212397_at 202838_at202069_s_at 212414_s_at 203058_s_at 202133_at 212419_at 203060_s_at202222_s_at 212464_s_at 203240_at 202242_at 212667_at 203296_s_at202274_at 212671_s_at 203343_at 202283_at 212713_at 203474_at202291_s_at 212730_at 203638_s_at 202388_at 212764_at 203963_at202555_s_at 212859_x_at 204018_x_at 202620_s_at 212956_at 204034_at202686_s_at 213068_at 204036_at 202746_at 213071_at 204130_at202760_s_at 213428_s_at 204388_s_at 202766_s_at 213509_x_at 204389_at202888_sat 213624_at 204508_s_at 202920_at 213746_s_at 204532_x_at202953_at 213891_s_at 204607_at 202957_at 214027_x_at 204673_at202992_at 214038_at 204818 _at 202994_s_at 214091_s_at 204895_x_at202995_s_at 214142_at 204897_at 203000_at 214414_x_at 205112_at203001_s_at 214505_s_at 205259_at 203066_at 214677_x_at 205403_at203131_at 214696_at 205480_s_at 203305_at 214752_x_at 205554_s_at203382_s_at 214768_x_at 205593_s_at 203477_at 214777_at 205892_s_at203645_s_at 215049_x_at 205929_at 203680_at 215076_s_at 206000_at203729_at 215118_s_at 206094_x_at 203748_x_at 215176_x_at 206262_at203766_s_at 215193_x_at 206377_at 203881_s_at 215382_x_at 206385_s_at203908_at 215388_s_at 206664_at 203913_s_at 215657_at 207126_x_at203914_x_at 216207_x_at 207245_at 203951_at 216401_x_at 207390_s_at203980_at 216442_x_at 207392_x_at 204069_at 216474_x_at 207432_at204083_s_at 216576_x_at 207761_s_at 204122_at 216834_at 208596_s_at204135_at 216984_x_at 208920_at 204326_x_at 217148_x_at 209114_at204438_at 217179_x_at 209374_s_at 204457_s_at 217235_x_at 209458_x_at204570_at 217258_x_at 209791_at 204688_at 217378_x_at 210107_at204697_s_at 217480_x_at 210524_x_at 204719_at 217546_at 210735_s_at204745_x_at 217757_at 211372_s_at 204834_at 217762_s_at 211538_s_at204894_s_at 217764_s_at 211549_s_at 204931_at 217767_at 211637_x_at204938_s_at 217897_at 211699_x_at 204939_s_at 217967_s_at 211745_x_at204940_at 218087_s_at 212224_at 204955_at 218162_at 212592_at 205097_at218224_at 212741_at 205200_at 218312_s_at 212814_at 205267_at 218353_at213317_at 205382_s_at 218418_s_at 21345 l_x_at 205412_at 218468_s_at213629_x_at 205433_at 218469_at 213921_at 205464_at 218559_s_at213953_at 205547_s_at 218756_s_at 214164_x_at 205683_x_at 219014_at214433_s_at 205935_at 219087_at 214598_at 205950_s_at 219508_at214916_x_at 206134_at 219607_s_at 215125_s_at 206143_at 219669_at215299_x_at 206149_at 219799_s_at 215867_x_at 206198_s_at 220026_at216336_x_at 206199_at 220037_s_at 216491_x_at 206208_at 220376_at216510_x_at 206209_s_at 220834_at 217022_s_at 206422_at 221541_at217109_at 206461_x_at 221667_s_at 217110_s_at 206561_s_at 221747_at217165_x_at 206576_s_at 221748_s_at 217232_x_at 206637_at 222043_at217414_x_at 206641_at 222162_s_at 218541_s_at 206710_s_at 222453_at218546_at 206784_at 222513_s_at 219059_s_at 207003_at 222717_at219543_at 207080_s_at 222722_at 219796_s_at 207134_x_at 223121_s_at219948_x_at 207266_x_at 223122_s_at 220075_s_at 207502_at 223235_s_at220266_s_at 207961_x_at 223343_at 220468_at 207977_s_at 223395_at220645_at 207980_s_at 223551_at 220812_s_at 208131_s_at 223623_at221004_s_at 208370_s_at 223952_x_at 221305_s_at 208383_s_at 224009_x_at221584_s_at 208399_s_at 224352_s_at 221841_s_at 208450_at 224412_s_at221896_s_at 208581_x_at 224480_s_at 223484_at 208747_s_at 224560_at223597_at 208763_s_at 224663_s_at 223754_at 208788_at 224694_at224342_x_at 208789_at 224823_at 224989_at 208791_at 224836_at 224990_at208792_s_at 224840_at 225458_at 208894_at 224959_at 225728_at 209047_at224963_at 226147_s_at 209074_s_at 224964_s_at 226302_at 209101_at225207_at 226594_at 209116_x_at 225242_s_at 226654_at 209138_x_at225269_s_at 226811_at 209147_s_at 225275_at 227052_at 209156_s_at225353_s_at 227522_at 209167_at 225381_at 227682_at 209170_s_at225442_at 227725_at 209191_at 225575_at 227735_s_at 209209_s_at225602_at 227736_at 209210_s_at 225604_s_at 228133_s_at 209283_at225626_at 228195_at 209301_at 225688_s_at 228232_s_at 209312_x_at225710_at 228241_at 209335_at 225720_at 228469_at 209357_at 225721_at228961_at 209373_at 225782_at 229070_at 209436_at 225894_at 229254_at209457_at 225895_at 229659_s_at 209496_at 226001_at 229831_at 209498_at226051_at 230595_at 209612_s_at 226084_at 231925_at 209613_s_at226103_at 231975_s_at 209621_s_at 226303_at 233565_s_at 209651_at226304_at 235146_at 209656_s_at 226333_at 235766_x_at 209667_at226430_at 235849_at 209668_x_at 226492_at 238143_at 209687_at 226682_at238750_at 209735_at 226694_at 238751_at 209763_at 226818_at 239272_at209868_s_at 226834_at 241994_at 209948_at 226841_at 242447_at210084_x_at 227006_at 242601_at 227099_s_at 227061_at 243278_at; and/or

-   -   (ii)

CLCA4 SGK MT1X ZG16 CFL2 AOC3 CA2 C1S PPAP2A CA1 SELENBP1 ZSCAN18 MS4A12MT1E IVD AQP 8 ADAMTS1 SFRP1 SLC4A4 ITM2A COL4A2 CEACAM7 POU2AF1 GPM6BTAGLN FAM55D EPB41L3 GUCA1B C6orf204 MAOA GCG AKAP12 DMD ADH1B TUBB6MSRB3 UGT2B17 LGALS2 PLOD2 ADAMDEC1 KIAA0828 C9orf19 MT1M MGC14376 MIER3AKR1B10 PPP1R14A XDH FN1 MUC4 CLDN23 MGP PKIB SGCE CXCL12 PIGR FOXF2PDK4 ASPN AGR3 CA4 A2M IGLJ3 PYY LOC25845 QKI IGHA1 LGALS1 LOC399959TPM2 BCHE ANKRD25 C6orf105 ST6GALNAC1 CRISPLD2 HPGD GJA1 ANK2 ADH1CSCNN1B LOC283666 CLCA1 FABP4 CRYAB FABP1 F13A1 ACAT1 ENAM CD36 IGL@ CFDSPARCL1 PBLD GUCA2B ZCWPW2 CCL8 FBLN1 TNC LIFR LOC63928 MT1A HLA-DRB1ABCA8 LOC652745 UGP2 POSTN MALL IGKV1D-13 DCN GNG2 AP1S2 ITLN1 DNASE1L3EMP3 COL6A2 EGR1 MMP28 FCGBP CMBL UGT2A3 SLC26A2 GCNT3 RGS5 PGM5SERPING1 PTGIS DMN MEIS1 DUSP5 GPNMB EDN3 MFAP4 IGFBP5 MSN UGT1A6 CLEC3BMT1G PRKAR2B LOC253012 TPSAB1 HHLA2 DPT GPX3 LOC652128 PCK1 CDKN2B C3CNN1 FOSB ATP2B4 HSD17B2 HSPA1A HBA1 PLAC8 CYBRD1 TCF21 TMEM47 PTGER4PPID OGN MAG1 PPAP2B CALD1 BEST2 SPON1 ACTG2 HLA-DQA1 PHLDB2 MGC4172PRIMA1 RARRES2 MAB21L2 MT1F ETHE1 RPL24 MAFB MMP2 ABCG2 FAM107A SRICCDC80 PRKACB CNTN3 UGT1A1 SELM RGS2 MRC1 TYROBP COL6A1 HSD11B2 TNS1FBN1 ANPEP MYH11 MXD1 MATN2 ITM2C PLCE1 PRNP CES2 KCNMB1 ABI3BP MS4A4ACALM1 HLA-C PDGFRA HLA-DPB1 NDE1 CA12 SMOC2 SRPX FKBP5 LOC285382 WWTR1HSPB8 CLIC5 HMGCS2 TPSB2 APOE LOC646627 FGL2 SERPINF1 KRT20 C1QBPPPIR12B KLF4 ANGPTL1 HSPB6 FHL1 MEP1A FNBP1 ARL14 GUCY1A3 C4orf34 LUMUGDH SORBS2 SORBS1 DUSP1 GPA33 METTL7A C2orf40 GALNAC4S-6ST FAM129A PLNCFHR1 SCARA5 UGT2B15 MGC13057 SI PDLIM3 C10orf56 ACTA2 TP53INP2 SULT1A1CD177 ATP8B1 TTRAP C10orf99 ANK3 CCL28 COL15A1 CTGF IDH3A NR3C2 MUCDHLEDG2 DHRS9 SDPR UGT1A8 LMOD1 COL14A1 RAB27A EFEMP1 DSCR1 ANTXR1 GREM1CITED2 EMP1 IL1R2 MT1H CSRP1 LOC387763 NEXN PLEKHC1 TIMP3 MUC2 LOC572558MYLK NID1 FOXP2 CLDN8 HBB HSPA2 RDX GCNT2 ATP1A2 TSPAN7 C20orf118 TNXBTNFRSF17 SLC20A1 FUCA1 SYNPO2 CD14 MRGPRF VIM KCTD12 HIGD1A SMPDL3ARBMS1 MFSD4 P2RY14 PTRF AXL CHGA TSPAN1 AQP1 C15orf48 UGT1A9 MAP1BCOL3A1 COX7A1 PALLD CYR61 MUC12 MPEG1 TRPM6 PDCD4 KLHL5 OSTbeta CAV1TCEAL7 IGLV1-44 FAM46C FILIP1L VSIG2 LRIG1 IQGAP2 IGHM HLA-DPA1 PRDX6LRRC19 C1orf115 RAB31 CD163 HBA2 LOC96610 CEACAM1 EDIL3 FGFR2 TIMP2 DESPAPSS2 ENTPD5 MT2A XLKD1 DDR2 KCNMA1 SMTN CHRDL1 GAS1 C8orf4 SRGN TBC1D9SDCBP2 PDE9A C7 CCL11 PMP22 P2RY1 ELOVL5 FLNA NR3C1 FOXF1 STMN2 STOMRELL1 MYL9 CKB PNMA1 SEMA6D CLU LOC339562 PADI2 SLC26A3 PALM2-AKAP2SEPP1 SDC2 PAG1 TGFB1I1 SST HCLS1 SFRP2 HLA-DRA RGS1 UGT1A3 TSC22D3FXYD6 MS4A7 IL6ST OLFML3 ALDH1A1 C1QC COL6A3in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state.

In one embodiment, said expression is assessed by screening for DNAchanges which impact on methylation, in particular hypermethylation. Inanother embodiment expression is assessed by the association of DNA withchromatin proteins carrying repressive modifications, for example,methylation of lysines 9 or 27 of the histone H3.

Reference to “large intestine” should be understood as a reference to acell derived from one of the six anatomical regions of the largeintestine, which regions commence after the terminal region of theileum, these being:

-   -   (i) the cecum;    -   (ii) the ascending colon;    -   (iii) the transverse colon;    -   (iv) the descending colon;    -   (v) the sigmoid colon; and    -   (vi) the rectum.

Reference to “neoplasm” should be understood as a reference to a lesion,tumour or other encapsulated or unencapsulated mass or other form ofgrowth which comprises neoplastic cells. A “neoplastic cell” should beunderstood as a reference to a cell exhibiting abnormal growth. The term“growth” should be understood in its broadest sense and includesreference to proliferation. In this regard, an example of abnormal cellgrowth is the uncontrolled proliferation of a cell. Another example isfailed apoptosis in a cell, thus prolonging its usual life span. Theneoplastic cell may be a benign cell or a malignant cell. In a preferredembodiment, the subject neoplasm is an adenoma or an adenocarcinoma.Without limiting the present invention to any one theory or mode ofaction, an adenoma is generally a benign tumour of epithelial originwhich is either derived from epithelial tissue or exhibits clearlydefined epithelial structures. These structures may take on a glandularappearance. It can comprise a malignant cell population within theadenoma, such as occurs with the progression of a benign adenoma to amalignant adenocarcinoma.

Preferably, said neoplastic cell is an adenoma or adenocarcinoma andeven more preferably a colorectal adenoma or adenocarcinoma.

Each of the genes and transcripts detailed in sub-paragraphs (i) and(ii), above, would be well known to the person of skill in the art, aswould their encoded proteins. The identification of the expressionproducts of these genes and transcripts as markers of neoplasia occurredby virtue of differential expression analysis using Affymetrix HGU133Aor HGU133B gene chips. To this end, each gene chip is characterised byapproximately 45,000 probe sets which detect the RNA transcribed fromthe genome. On average, approximately 11 probe pairs detect overlappingor consecutive regions of the RNA transcript. In general, the genes fromwhich the RNA transcripts described herein are identifiable by theAffymetrix probesets are well known and characterised genes. However, tothe extent that some of the probesets detect RNA transcripts which arenot yet defined, these transcripts are indicated as “the gene, genes ortranscripts detected by Affymetrix probe x”. In some cases a number ofgenes may be detectable by a single probeset. It should be understood,however, that this is not intended as a limitation as to how theexpression level of the subject gene or transcript can be detected. Inthe first instance, it would be understood that the subject genetranscript is also detectable by other probesets which would be presenton the Affymetrix gene chip. The reference to a single probeset ismerely included as an identifier of the gene transcript of interest. Interms of actually screening for the transcript, however, one may utilisea probe or probeset directed to any region of the transcript and notjust to the 3-terminal 600 bp transcript region to which the Affymetrixprobes are often directed.

Reference to each of the genes and transcripts detailed above and theirtranscribed and translated expression products should therefore beunderstood as a reference to all forms of these molecules and tofragments or variants thereof. As would be appreciated by the person ofskill in the art, some genes are known to exhibit allelic variationbetween individuals. Accordingly, the present invention should beunderstood to extend to such variants which, in terms of the presentdiagnostic applications, achieve the same outcome despite the fact thatminor genetic variants between the actual nucleic acid sequences mayexist between individuals or that within one individual there may exist2 or more splice variants of the subject gene. The present inventionshould therefore be understood to extend to all forms of RNA (eg mRNA,primary RNA transcript, miRNA, etc), cDNA and peptide isoforms whicharise from alternative splicing or any other mutation, polymorphic orallelic variation. It should also be understood to include reference toany subunit polypeptides such as precursor forms which may be generated,whether existing as a monomer, multimer, fusion protein or othercomplex.

To this end, in terms of the genes encompassed by the present invention,means for determining the existence of such variants, and characterisingsame, are described in Example 6. To the extent that the genes of thepresent invention are described by reference to an Affymetrix probeset,Table 6 provides details of the nucleic acid sequence to which eachprobe set is directed. Based on this information, the skilled personcould, as a matter of routine procedure, identify the gene in respect ofwhich that sequence forms part. A typical protocol for doing this isalso outlined in Example 6.

It should be understood that the “individual” who is the subject oftesting may be any human or non-human mammal. Examples of non-humanmammals includes primates, livestock animals (e.g. horses, cattle,sheep, pigs, donkeys), laboratory test animals (e.g. mice, rats,rabbits, guinea pigs), companion animals (e.g. dogs, cats) and captivewild animals (e.g. deer, foxes). Preferably the mammal is a human.

The method of the present invention is predicated on the comparison ofthe level of the neoplastic markers of a biological sample with thecontrol levels of these markers. The “control level” may be either a“normal level”, which is the level of marker expressed by acorresponding large intestine cell or cellular population which is notneoplastic.

The normal (or “non-neoplastic”) level may be determined using tissuesderived from the same individual who is the subject of testing. However,it would be appreciated that this may be quite invasive for theindividual concerned and it is therefore likely to be more convenient toanalyse the test results relative to a standard result which reflectsindividual or collective results obtained from individuals other thanthe patient in issue. This latter form of analysis is in fact thepreferred method of analysis since it enables the design of kits whichrequire the collection and analysis of a single biological sample, beinga test sample of interest. The standard results which provide the normallevel may be calculated by any suitable means which would be well knownto the person of skill in the art. For example, a population of normaltissues can be assessed in terms of the level of the neoplastic markersof the present invention, thereby providing a standard value or range ofvalues against which all future test samples are analysed. It shouldalso be understood that the normal level may be determined from thesubjects of a specific cohort and for use with respect to test samplesderived from that cohort. Accordingly, there may be determined a numberof standard values or ranges which correspond to cohorts which differ inrespect of characteristics such as age, gender, ethnicity or healthstatus. Said “normal level” may be a discrete level or a range oflevels. A decrease in the expression level of the subject genes relativeto normal levels is indicative of the tissue being neoplastic.

Without limiting the present invention to any one theory or mode ofaction, although each of the genes or transcripts hereinbefore describedis differentially expressed, either singly or in combination, as betweenneoplastic versus non-neoplastic cells of the large intestine, and istherefore diagnostic of the existence of a large intestine neoplasm, theexpression of some of these genes was found to exhibit particularlysignificant levels of sensitivity, specificity and positive and negativepredictive value. Accordingly, in a preferred embodiment one wouldscreen for and assess the expression level of one or more of thesegenes. To this end, and without limiting the present invention to anyone theory or mode of action, the following markers were determined tobe expressed in neoplastic tissue at a level of 3-11 fold less thannon-neoplastic tissue, when assessed by virtue of the method exemplifiedherein:

Gene, genes or transcripts detected Fold by Affymetrix Decrease ProbeNo: Gene 11 220026_at CLCA4 10 214142_at ZG16 9 209301_at CA1205950_s_at CA2 8 220834_at MS4A12 7 206784_at AQP8 6 203908_at SLC4A4206198_s_at CEACAM7 205547_s_at TAGLN 207003_at GUCA1B 206422_at GCG209613_s_at ADH1B 207245_at UGT2B17 5 206134_at ADAMDEC1 217546_at MT1M206561_s_at AKR1B10 211719_x_at FN1 202291_s_at MGP 209687_at CXCL12 4225207_ at PDK4 206208_at CA4 207080_s_at PYY 215118_s_at IGHA1204083_s_at TPM2 229070_at C6orf105 211548_s_at HPGD 206262_at ADH1C210107_at CLCA1 205892_s_at FABP1 212592_at ENAM 205382_s_at CFD207502_at GUCA2B 202995_s_at FBLN1 206149_at LOC63928 204719_at ABCA8 3210809_s_at POSTN 201893_x_at DCN 223597_at ITLN1 209156_s_at COL6A2203240_at FCGBP 224963_at SLC26A2 226303_at PGM5 212730_at DMN 201141_atGPNMB 211959_at IGFBP5 205200_at CLEC3B 242601_at LOC253012 213068_atDPT 208383_s_at PCK1 203951_at CNN1 204818_at HSD17B2 219014_at PLAC8209656_s_at TMEM47 222722_at OGN 201617_x_at CALD1 202274_at ACTG2218756_s_at MGC4172 210302_s_at MAB21L2 228885_at RPL24 209735_at ABCG2228504_at CCDC80 225242_s_at UGT1A1 215125_s_at MRC1 204438_at HSD11B2204130_at ANPEP 202888_s_at MATN2 202350_s_at PRNP 201300_s_at ABI3BP223395_at HLA-C 214768_x_at NDE1 228133_s_at SRPX 204955_at WWTR1202133_at HMGCS2 204607_at LOC646627 238143_at KRT20 213953_at KLF4220266_s_at FHL1 210299_s_at ARL14 220468_at LUM 201744_s_at SORBS1218087_s_at METTL7A 207761_s_at FAM129A 217967_s_at SCARA5 229839_at SI206664_at ACTA2 200974_at CD177 219669_at C10orf99 227736_at COL15A1203477_at NR3C2 205259_at

There is therefore more particularly provided a method of screening forthe onset or predisposition to the onset of a large intestine neoplasmin an individual, said method comprising assessing the level ofexpression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 220026_at; and/or    -   (ii) CLCA4        in a biological sample from said individual wherein a lower        level of expression of the gene or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In another embodiment, there is provided a method of screening for theonset or predisposition to the onset of a large intestine neoplasm in anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 214142_at; and/or    -   (ii) ZG16        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In yet another embodiment there is provided a method of screening forthe onset or predisposition to the onset of a large intestine neoplasmin an individual, said method comprising assessing the level ofexpression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

209301_at 205950_s_at; and/or

-   -   (ii)

CA2 CA1in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In still yet another preferred embodiment, there is provided a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising assessingthe level of expression of one or more genes or transcripts selectedfrom:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 220834_at; and/or    -   (ii) MS4A12        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In yet still another preferred embodiment, there is provided a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising assessingthe level of expression of one or more genes or transcripts selectedfrom:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 206784 at; and/or    -   (ii) AQP8        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In a further embodiment, there is provided a method of screening for theonset or predisposition to the onset of a large intestine neoplasm in anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   (i) (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 203908_at, 206198_s_at, 205547_s_at, 207003_at,        206422_at, 209613_s_at, 207245_at; and/or    -   (ii) SLC4A4, CEACAM7, TAGLN, GUCA1B, GCG, ADH1B, UGT2B17        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In another further embodiment, there is provided a method of screeningfor the onset or predisposition to the onset of a large intestineneoplasm in an individual, said method comprising assessing the level ofexpression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset 206134_at, 217546_at, 206561_s_at, 211719_x_at,        202291_s_at, 209687_at; and/or    -   (ii) ADAMDEC1, MTIM, AKR1B10, FN1, MGP, CXCL12        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to control levels is indicative of a        neoplastic large intestine cell or a cell predisposed to the        onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In still another further embodiment, there is provided a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising screeningthe level of expression of one or more genes or transcripts selectedfrom:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

225207_at 211548_s_at 205382_s_at 206208_at 206262_at 207502_at207080_s_at 210107_at 202995_s_at 215118_s_at 205892_s_at 206149_at204083_s_at 212592_at 204719_at 229070_at; and/or

-   -   (ii)

PDK4 HPGD CFD CA4 ADH1C GUCA2B PYY CLCA1 FBLN1 IGHA1 FABP1 LOC63928 TPM2ENAM ABCA8 C6orf105in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

In yet still yet another further embodiment, there is provided a methodof screening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising screeningthe level of expression of one or more genes or transcripts selectedfrom:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

210809_s_at 201617_x_at 202133_at 201893_x_at 202274_at 204607_at223597_at 218756_s_at 238143_at 209156_s_at 210302_s_at 213953_at203240_at 228885_at 220266_s_at 224963_at 209735_at 210299_s_at226303_at 228504_at 220468_at 212730_at 225242_s_at 201744_s_at201141_at 215125_s_at 218087_s_at 211959_at 204438_at 207761_s_at205200_at 204130_at 217967_s_at 242601_at 202888_s_at 229839_at213068_at 202350_s_at 206664_at 208383_s_at 201300_s_at 200974_at203951_at 223395_at 219669_at 204818_at 214768_x_at 227736_at 219014_at228133_s_at 203477_at 209656_s_at 204955_at 205259_at 222722_at; and/or

-   -   (ii)

POSTN OGN WWTR1 DCN CALD1 HMGCS2 ITLN1 ACTG2 LOC646627 COL6A2 MGC4172KRT20 FCGBP MAB21L2 KLF4 SLC26A2 RPL24 FHL1 PGM5 ABCG2 ARL14 DMN CCDC80LUM GPNMB UGT1A1 SORBS1 IGFBP5 MRC1 METTL7A CLEC3B HSD11B2 FAM129ALOC253012 ANPEP SCARA5 DPT MATN2 SI PCK1 PRNP ACTA2 CNN1 ABI3BP CD177HSD17B2 HLA-C C10orf99 PLAC8 NDE1 COL15A1 TMEM47 SRPX NR3C2in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state.

Preferably, said control level is a non-neoplastic level.

According to these aspects of the present invention, said largeintestine tissue is preferably colorectal tissue.

In one embodiment, said expression is assessed by screening for DNAchanges which impact on methylation, in particular hypermethylation. Inanother embodiment, expression is assessed by the association of DNAwith chromatin proteins carrying repressive modifications, for example,methylation of lysines 9 or 27 of histone H3.

The detection method of the present invention can be performed on anysuitable biological sample. To this end, reference to a “biologicalsample” should be understood as a reference to any sample of biologicalmaterial derived from an animal such as, but not limited to, cellularmaterial, biofluids (eg. blood), faeces, tissue specimens (such asbiopsy specimens), surgical specimens or fluid which has been introducedinto the body of an animal and subsequently removed (such as, forexample, the solution retrieved from an enema wash). The biologicalsample which is tested according to the method of the present inventionmay be tested directly or may require some form of treatment prior totesting. For example, a biopsy or surgical sample may requirehomogenisation prior to testing or it may require sectioning for in situtesting of the qualitative expression levels of individual genes.Alternatively, a cell sample may require permeabilisation prior totesting. Further, to the extent that the biological sample is not inliquid form, (if such form is required for testing) it may require theaddition of a reagent, such as a buffer, to mobilise the sample.

To the extent that the neoplastic marker gene expression product ispresent in a biological sample, the biological sample may be directlytested or else all or some of the nucleic acid material present in thebiological sample may be isolated prior to testing. In yet anotherexample, the sample may be partially purified or otherwise enrichedprior to analysis. For example, to the extent that a biological samplecomprises a very diverse cell population, it may be desirable to enrichfor a sub-population of particular interest. It is within the scope ofthe present invention for the target cell population or moleculesderived therefrom to be pretreated prior to testing, for example,inactivation of live virus or being run on a gel. It should also beunderstood that the biological sample may be freshly harvested or it mayhave been stored (for example by freezing) prior to testing or otherwisetreated prior to testing (such as by undergoing culturing).

The choice of what type of sample is most suitable for testing inaccordance with the method disclosed herein will be dependent on thenature of the situation. Preferably, said sample is a faecal (stool)sample, enema wash, surgical resection, tissue or blood specimen.

In a related aspect, it has been determined that certain of the markershereinbefore defined are more indicative of adenoma development versuscancer development or vice versa. This is an extremely valuable findingsince it enables one to more specifically characterise the likely natureof a neoplasm which is detected by virtue of the method of the presentinvention.

Accordingly, in a related aspect the present invention is directed to amethod of screening for the onset or predisposition to the onset of alarge intestine neoplasm in an individual, said method comprisingscreening the level of expression of one or more genes or transcriptsselected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

200600_at 208788_at 215382_x_at 200665_s_at 208789_at 215388_s_at200799_at 208894_at 216442_x_at 200845_s_at 209047_at 216474_x_at200859_x_at 209101_at 216834_at 200897_s_at 209138_x_at 217480_x_at200974_at 209147_s_at 217757_at 200986_at 209156_s_at 217762_s_at201041_s_at 209191_at 217764_s_at 201061_s_at 209209_s_at 217767_at201069_at 209210_s_at 217897_at 201105_at 209312_x_at 218162_at201137_s_at 209335_at 218224_at 201141_at 209436_at 218312_s_at201150_s_at 209457_at 218353_at 201289_at 209496_at 218418_s_at201300_s_at 209621_s_at 218468_s_at 201426_s_at 209651_at 218469_at201438_at 209656_s_at 218559_s_at 201616_s_at 209868_s_at 219087_at201617_x_at 210084_x_at 219607_s_at 201645_at 210133_at 221541_at201667_at 210139_s_at 222043_at 201743_at 210495_x_at 222453_at201744_s_at 210517_s_at 222513_s_at 201842_s_at 210764_s_at 223121_s_at201852_x_at 210809_s_at 223122_s_at 201858_s_at 210982_s_at 223235_s_at201859_at 211161_s_at 223343_at 201865_x_at 211596_s_at 224560_at201893_x_at 211671_s_at 224694_at 201920_at 211719_x_at 224840_at202007_at 211813_x_at 224964_s_at 202069_s_at 211896_s_at 225242_s_at202133_at 211959_at 225269_s_at 202283_at 211964_at 225353_s_at202291_s_at 211985_s_at 225381_at 202403_s_at 211990_at 225442_at202620_s_at 211991_s_at 225602_at 202686_s_at 212077_at 225604_s_at202760_s_at 212091_s_at 225626_at 202766_s_at 212136_at 225688_s_at202953_at 212158_at 225710_at 202957_at 212185_x_at 226001_at202994_s_at 212195_at 226051_at 202995_s_at 212230_at 226084_at203066_at 212233_at 226103_at 203131_at 212265_at 226430_at 203305_at212386_at 226682_at 203382_s_at 212387_at 226694_at 203477_at 212397_at226818_at 203645_s_at 212414_s_at 226834_at 203680_at 212419_at226841_at 203729_at 212464_s_at 227061_at 203748_x_at 212667_at227099_s_at 204069_at 212671_s_at 227235_at 204122_at 212713_at227404_s_at 204135_at 212764_at 227529_s_at 204438_at 212956_at227561_at 204457_s_at 213428_s_at 227623_at 204570_at 213509_x_at227705_at 204688_at 213746_s_at 227727_at 205412_at 213891_s_at228507_at 205683_x_at 214038_at 228750_at 205935_at 214677_x_at228846_at 207134_x_at 214752_x_at 229530_at 207266_x_at 215049_x_at230264_s_at 208131_s_at 215076_s_at 231579_s_at 208370_s_at 215193_x_at234987_at; and/or 208747_s_at

-   -   (ii)

A2M FBN1 PALLD ACAT1 FILIP1L PALM2-AKAP2 ACTA2 FKBP5 PDGFRA AKAP12 FLNAPDLIM3 ANKRD25 FN1 PHLDB2 ANTXR1 FOXF1 PLEKHC1 AP1S2 FXYD6 PLOD2 APOEGALNAC4S-6ST PMP22 AQP1 GAS1 PNMA1 ASPN GJA1 POSTN ATP2B4 GNG2 PPAP2AAXL GPNMB PPAP2B C10orf56 GREM1 PRDX6 C1QB GUCY1A3 PRKAR2B C1QC HCLS1PRNP C1S HLA-DPA1 PTGIS C20orf118 HLA-DPB1 PTRF C3 HLA-DQA1 QKI C9orf19HLA-DRA RAB31 CALD1 HLA-DRB1 RARRES2 CALM1 HSPA1A RBMS1 CCDC80 IDH3A RDXCCL11 IGFBP5 RELL1 CCL8 IGL@ RGS1 CD14 IGLJ3 RGS5 CD163 IL6ST SDC2 CES2KLHL5 SELM CFHR1 LGALS1 SEPT6 CLU LOC283666 SERPINF1 COL14A1 LOC339562SERPING1 COL15A1 LOC387763 SFRP2 COL1A2 LOC399959 SGCE COL3A1 LRIG1SLC20A1 COL4A2 LUM SMOC2 COL6A1 MAFB SORBS1 COL6A2 MAP1B SPARC COL6A3MEIS1 SPON1 COX7A1 MFAP4 SRGN CRISPLD2 MGP STOM CTGF MMP2 TBC1D9 CYBRD1MPEG1 TCEAL7 CYR61 MRC1 TGFB1I1 DCN MRGPRF TIMP2 DDR2 MS4A4A TIMP3 DSCR1MS4A7 TMEM47 DUSP1 MSN TNC DUSP5 MT2A TPSAB1 EFEMP1 MXD1 TPSB2 EGR1 NEXNTUBB6 ELOVL5 NID1 TYROBP EMP3 NR3C1 VIM F13A1 OLFML3 WWTR1 FBLN1 PAG1ZSCAN18in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of an adenoma cell or a cellpredisposed to the onset of an adenoma state.

In another preferred embodiment of this aspect of the present inventionthere is provided a method of screening for the onset or predispositionto the onset of a large intestine neoplasm in an individual, said methodcomprising screening the level, of expression done or more genes ortranscripts selected from:

-   -   (i) the gene or genes detected by Affymetrix probeset IDs:

200884_at 208596_s_at 220812_s_at 201495_x_at 208920_at 221004_s_at202266_at 209114_at 221305_s_at 202350_s_at 209374_s_at 221584_s_at202731_at 209458_x_at 221841_s_at 202741_at 209791_at 221896_s_at202742_s_at 210107_at 223484_at 202768_at 210524_x_at 223597_at202838_at 210735_s_at 223754_at 203058_s_at 211372_s_at 224342_x_at203060_s_at 211538_s_at 224989_at 203240_at 211549_s_at 224990_at203296_s_at 211637_x_at 225458_at 203343_at 211699_x_at 225728_at203474_at 211745_x_at 226147_s_at 203638_s_at 212224_at 226302_at203963_at 212592_at 226594_at 204018_x_at 212741_at 226654_at 204034_at212814_at 226811_at 204036_at 213317_at 227052_at 204130_at 213451_x_at227522_at 204388_s_at 213629_x_at 227682_at 204389_at 213921_at227725_at 204508_s_at 213953_at 227735_s_at 204532_x_at 214164_x_at227736_at 204607_at 214433_s_at 228133_s_at 204673_at 214598_at228195_at 204818_at 214916_x_at 228232_s_at 204895_x_at 215125_s_at228241_at 204897_at 215299_x_at 228469_at 205112_at 215867_x_at228961_at 205259_at 216336_x_at 229070_at 205403_at 216491_x_at229254_at 205480_s_at 216510_x_at 229659_s_at 205554_s_at 217022_s_at229831_at 205593_s_at 217109_at 230595_at 205892_s_at 217110_s_at231925_at 205929_at 217165_x_at 231975_s_at 206000_at 217232_x_at233565_s_at 206094_x_at 217414_x_at 235146_at 206262_at 218541_s_at235766_x_at 206377_at 218546_at 235849_at 206385_s_at 219059_s_at238143_at 206664_at 219543_at 238750_at 207126_x_at 219796_s_at238751_at 207245_at 219948_x_at 239272_at 207390_s_at 220075_s_at241994_at 207392_x_at 220266_s_at 242447_at 207432_at 220468_at242601_at 207761_s_at 220645_at 243278_at; and/or

-   -   (ii)

ADH1C HIGD1A NRC2 AGR3 HMGCS2 P2RY1 ALDH1A1 HPGD PADI2 ANK3 HSD11B2PAPSS2 ARL14 HSD17B2 PBLD ATP1A2 HSPA2 PDCD4 ATP8B1 IGHA1 PDE9A BEST2IGHM PIGR C10orf99 IL1R2 PLCE1 C15orf48 IL8 PPID C1orf115 IQGAP2 PRKACBC4orf34 ITLN1 PTGER4 C6orf105 ITM2C RAB27A C8orf4 KCNMA1 SCARA5 CA12KIAA0828 SDCBP2 CCL28 KLF4 SELENBP1 CKB KRT20 SI CLCA1 LOC253012 SMTNCLDN8 LOC25845 SORBS2 CLIC5 LOC285382 SRI CMBL LOC572558 SST CNTN3LOC646627 ST6GALNAC1 DNASE1L3 LOC652128 SULT1A1 EDG2 LOC96610 TNXB ENAMMAOA TSPAN1 ENTPD5 MATN2 TTRAP ETHE1 MEP1A UGDH FABP1 METTL7A UGP2FAM46C MFSD4 UGT1A1 FAM55D MGC13057 UGT1A3 FCGBP MIER3 UGT1A6 FGFR2MMP28 UGT1A8 FOSB MT1A UGT1A9 FOXF2 MT1F UGT2A3 FOXP2 MT1M UGT2B15 FUCA1MUC12 UGT2B17 GPA33 MUC2 VSIG2 HBA1 MUC4 XDH HBA2 MUCDHL XLKD1 HBB MYH11ZCWPW2 HHLA2 NDE1in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a cancer cell or a cellpredisposed to the onset of a cancerous state.

According to these aspects, said control levels are preferablynon-neoplastic levels and said large intestine tissue is colorectaltissue. Even more preferably, said biological sample is a stool sampleor blood sample.

In one embodiment, said expression is assessed by screening for DNAchanges which impact on methylation, in particular hypermethylation. Inanother embodiment, expression is assessed by the association of DNAwith chromatin proteins carrying repressive modifications, for example,methylation of lysines 9 or 27 of histone H3.

In a related aspect, it has been determined that a subpopulation of themarkers of the present invention are not only expressed at levels lowerthan normal levels, their expression pattern is uniquely characterisedby the fact that expression levels above that of background controllevels are not detectable in neoplastic tissue. This determination hastherefore enabled the development of qualitative screening systems whichare simply designed to detect marker expression relative to a controlbackground level. In accordance with this aspect of the presentinvention, said “control level” is therefore the “background level”.

According to this aspect, there is therefore provided a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising screeningthe level of expression of one or more genes or transcripts selectedfrom:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

202920_at 222717_at 231120_x_at 203881_s_at 224412_s_at 231773_at204719_at 225381_at 203296_s_at 204931_at 225575_at 206664_at 204940_at227529_s_at 211549_s_at 205433_at 227623_at 214598_at 206637_at227705_at 219948_x_at 207080_s_at 227827_at 220812_s_at 207980_s_at228504_at 221305_s_at 209170_s_at 228706_s_at 229831_at 209209_s_at228766_at 231925_at 209613_s_at 228854_at 235146_at 220037_s_at228885_at 238751_at 220376_at 230788_at 243278_at; and/or

-   -   (ii)

ADH1B ANGPTL1 HHLA2 SORBS2 DMD SORBS2 PYY GCNT2 CLDN23 ABCA8 SDPR CNTN3RPL24 PKIB PLEKC1 SI CITED2 LRRC19 CLDN8 TCF21 LIFR P2RY14 P2RY1 ATP1A2PLN ANK2 HPGD TRPM6 XLKD1 GPM6B CD36 LOC399959 UGT1A8 BCHE AKAP12 FOXP2TCEAL7 UGT2A3in a biological sample from said individual wherein a level ofexpression of the genes or transcripts of group (i) and/or group (ii)which is not substantially above background levels is indicative of aneoplastic cell or a cell predisposed to the onset of a neoplasticstate.

In a most preferred embodiment, said genes or transcripts are selectedfrom:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 209613_s_at, 227827 at, 204719_at, 228504_at,        228885_at, 206664_at, 207080_s_at; and/or    -   (ii) ADH1B, SORBS2, PYY, ABCA8, RPL24, SI

Preferably, said neoplasm is an adenoma or an adenocarcinoma and saidgastrointestinal tissue is colorectal tissue.

In yet another embodiment, it has been determined that a furthersubpopulation of these markers are more characteristic of adenomadevelopment, while others are more characteristic of cancer development.Accordingly, there is provided a convenient means of qualitativelyobtaining indicative information in relation to the characteristics ofthe subject neoplasm.

According to this embodiment there is provided a method of screening forthe onset or predisposition to the onset of a large intestine neoplasmin an individual, said method comprising screening the level ofexpression of one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 209209_s_at, 225381_at, 227529_s_at, 227623_at,        227705_at; and/or    -   (ii) AKAP12, LOC399959, PLEKHC1, TCEAL7        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) which is not substantially above background        levels is indicative of an adenoma cell or a cell predisposed to        the onset of an adenoma state.

In yet still another preferred embodiment there is provided a method ofscreening for the onset or predisposition to the onset of a largeintestine neoplasm in an individual, said method comprising screeningthe level of expression of one or more genes or transcripts selectedfrom:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

203296_s_at 219948_x_at 231925_at 206664_at 220812_s_at 235146_at211549_s_at 221305_s_at 238751_at 214598_at 229831_at 243278_at; and/or

-   -   (ii)

ATP1A2 HHLA2 SORBS2 CLDN8 HPGD UGT1A8 CNTN3 P2RY1 UGT2A3 FOXP2 SIin a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)which is not substantially above background levels is indicative of acancer cell or a cell predisposed to the onset of a cancerous state.

Preferably, said large intestine tissue is colorectal tissue.

More preferably, said biological sample is a stool sample or a bloodsample.

In one embodiment, said expression is assessed by screening for DNAchanges which impact on methylation, in particular hypermethylation. Inanother embodiment, expression is assessed by the association of DNAwith chromatin proteins carrying repressive modifications, for example,methylation of lysines 9 or 27 of histone H3.

As detailed hereinbefore, the present invention is designed to screenfor a neoplastic cell or cellular population, which is located in thelarge intestine. Accordingly, reference to “cell or cellular population”should be understood as a reference to an individual cell or a group ofcells. Said group of cells may be a diffuse population of cells, a cellsuspension, an encapsulated population of cells or a population of cellswhich take the form of tissue.

Reference to “expression” should be understood as a reference to thetranscription and/or translation of a nucleic acid molecule. In thisregard, the present invention is exemplified with respect to screeningfor neoplastic marker expression products taking the form of RNAtranscripts (eg primary RNA or mRNA). Reference to “RNA” should beunderstood to encompass reference to any form of RNA, such as primaryRNA or mRNA. Without limiting the present invention in any way, themodulation of gene transcription leading to increased or decreased RNAsynthesis will also correlate with the translation of some of these RNAtranscripts (such as mRNA) to produce a protein product. Accordingly,the present invention also extends to detection methodology which isdirected to screening for modulated levels or patterns of the neoplasticmarker protein products as an indicator of the neoplastic state of acell or cellular population. Although one method is to screen for mRNAtranscripts and/or the corresponding protein product, it should beunderstood that the present invention is not limited in this regard andextends to screening for any other form of neoplastic marker expressionproduct such as, for example, a primary RNA transcript.

In terms of screening for the downregulation of expression of a markerit would also be well known to the person of skill in the art thatchanges which are detectable at the DNA level are indicative of changesto gene expression activity and therefore changes to expression productlevels. Such changes include but are not limited to, changes to DNAmethylation. Accordingly, reference herein to “screening the level ofexpression” and comparison of these “levels of expression” to control“levels of expression” should be understood as a reference to assessingDNA factors which are related to transcription, such as gene/DNAmethylation patterns.

It would also be known to a person skilled in the art that changes inthe structure of chromatin are indicative of changes in gene expression.Silencing of gene expression is often associated with modification ofchromatin proteins, methylation of lysines at either or both positions 9and 27 of histone H3 being well studied examples, while active chromatinis marked by acetylation of lysine 9 of histone H3. Thus association ofgene sequences with chromatin carrying repressive or activemodifications can be used to make an assessment of the expression levelof a gene.

It is well within the skill of the person of skill in the art todetermine the most appropriate screening method for any given situation.To this end, the genes which are known to encode an expression productwhich is either secreted by the cell or membrane bound is detailed inthe table below. It would be appreciated that screening for neoplasticmarkers which are secreted or membrane bound may provide particularadvantages in terms of the design of a diagnostic screening product.

The gene or genes detected by Affymetrix probe Nos: 200600_at205593_s_at 212185_x_at 224480_s_at 200845_s_at 205765_at 212192_at224663_s_at 200859_x_at 205892_s_at 212224_at 224694_at 200884_at205927_s_at 212230_at 224823_at 200897_s_at 205929_at 212233_at224836_at 200974_at 205935_at 212265_at 224840_at 201041_s_at 205935_at212288_at 224959_at 201058_s_at 205950_s_at 212386_at 224963_at201061_s_at 206000_at 212387_at 224964_s_at 201069_at 206094_x_at212397_at 224989_at 201105_at 206143_at 212414_s_at 224990_at201137_s_at 206149_at 212419_at 225207_at 201300_s_at 206198_s_at212671_s_at 225242_s_at 201324_at 206199_at 212730_at 225269_s_at201426_s_at 206208_at 212741_at 225381_at 201539_s_at 206209_s_at212764_at 225442_at 201540_at 206262_at 212814_at 225458_at 201616_s_at206377_at 212859_x_at 225575_at 201617_x_at 206385_s_at 212956_at225602_at 201667_at 206461_x_at 213106_at 225604_s_at 201739_at206561_s_at 213317_at 225626_at 201743_at 206576_s_at 213509_x_at225710_at 201865_x_at 206637_at 213629_x_at 225720_at 201920_at206664_at 213746_s_at 225721_at 201957_at 206710_s_at 213891_s_at225782_at 202007_at 206784_at 213953_at 225894_at 202069_s_at207126_x_at 214027_x_at 225895_at 202133_at 207245_at 214234_s_at226001_at 202242_at 207266_x_at 214235_at 226051_at 202266_at207390_s_at 214414_x_at 226084_at 202274_at 207392_x_at 214433_s_at226103_at 202388_at 207432_at 214505_s_at 226147_at 202555_s_at207761_s_at 214598_at 226248_s_at 202620_s_at 207980_s_at 214677_x_at226302_at 202686_s_at 208063_s_at 214696_at 226303_at 202731_at208131_s_at 214752_x_at 226304_at 202741_at 208370_s_at 214768_x_at226333_at 202742_s_at 208383_s_at 214777_at 226430_at 202746_at208450_at 215049_x_at 226594_at 202760_s_at 208581_x_at 215118_s_at226654_at 202768_at 208596_s_at 215125_s_at 226682_at 202888_s_at208763_s_at 215176_x_at 226694_at 202920_at 208788_at 215193_x_at226811_at 202957_at 208789_at 215299_x_at 226818_at 202992_at 208920_at215657_at 226834_at 202994_s_at 208937_s_at 216207_x_at 226841_at202995_s_at 209047_at 216336_x_at 227006_at 203000_at 209074_s_at216401_x_at 227052_at 203001_s_at 209114_at 216491_x_at 227061_at203058_s_at 209116_x_at 216576_x_at 227099_s_at 203060_s_at 209138_x_at216834_at 227235_at 203066_at 209147_s_at 216984_x_at 227404_s_at203131_at 209156_s_at 217022_s_at 227522_at 203240_at 209167_at217148_x_at 227529_s_at 203305_at 209170_s_at 217165_x_at 227561_at203343_at 209191_at 217232_x_at 227623_at 203382_s_at 209209_s_at217235_x_at 227662_at 203474_at 209210_s_at 217378_x_at 227682_at203638_s_at 209283_at 217414_x_at 227705_at 203645_s_at 209301_at217480_x_at 227719_at 203680_at 209312_x_at 217546_at 227725_at203729_at 209357_at 217762_s_at 227727_at 203748_x_at 209373_at217764_s_at 227735_s_at 203766_s_at 209374_s_at 217897_at 227736_at203908_at 209457_at 217967_s_at 228202_at 203913_s_at 209458_x_at218087_s_at 228232_s_at 203914_x_at 209498_at 218211_s_at 228469_at203951_at 209612_s_at 218224_at 228504_at 203980_at 209613_s_at218312_s_at 228507_at 204018_x_at 209621_s_at 218353_at 228640_at204034_at 209651_at 218418_s_at 228766_at 204036_at 209656_s_at218546_at 228846_at 204069_at 209667_at 218559_s_at 228854_at204083_s_at 209668_x_at 219014_at 228961_at 204122_at 209868_s_at219059_s_at 229070_at 204130_at 209948_at 219508_at 229254_at 204135_at210107_at 219543_at 229530_at 204326_x_at 210139_s_at 219607_s_at229659_s_at 204388_s_at 210298_x_at 219796_s_at 229831_at 204389_at210299_s_at 219948_x_at 229839_at 204438_at 210302_s_at 219955_at230087_at 204457_s_at 210517_s_at 220026_at 230264_s_at 204532_x_at210524_x_at 220037_s_at 230595_at 204570_at 210524_x_at 220075_s_at230788_at 204607_at 210946_at 220266_s_at 230830_at 204688_at211372_s_at 220376_at 231120_x_at 204697_s_at 211538_s_at 220468_at231832_at 204719_at 211548_s_at 220812_s_at 231925_at 204745_x_at211549_s_at 220834_at 231975_s_at 204818_at 211596_s_at 221004_s_at232176_at 204894_s_at 211637_x_at 221305_s_at 232481_s_at 204897_at211643_x_at 221667_s_at 233565_s_at 204931_at 211645_x_at 221747_at234987_at 204938_s_at 211671_s_at 221748_s_at 235146_at 204939_s_at211696_x_at 221841_s_at 235766_x_at 204940_at 211699_x_at 221874_at235849_at 204955_at 211745_x_at 221896_s_at 235976_at 205097_at211798_x_at 222513_s_at 236300_at 205112_at 211848_s_at 222717_at236313_at 205259_at 211889_x_at 223235_s_at 236894_at 205267_at211964_at 223343_at 237521_x_at 205403_at 211985_s_at 223395_at238750_at 205412_at 211990_at 223484_at 241994_at 205433_at 211991_s_at223551_at 242317_at 205464_at 212077_at 223597_at 242447_at 205480_s_at212097_at 223623_at 242601_at 205547_s_at 212136_at 224352_s_at243278_at 205554_s_at 212158_at 224412_s_at ABCA8 EGR1 LOC25845 PPIDABI3BP ELOVL5 LOC283666 PPP1R12B ACAT1 EMP1 LOC285382 PPP1R14A ACTA2EMP3 LOC339562 PRDX6 ACTG2 ENTPD5 LOC387763 PRIMA1 ADH1B EPB41L3LOC399959 PRKACB ADH1C ETHE1 LOC572558 PRKAR2B AKAP12 F13A1 LOC63928PRNP AKR1B10 FABP1 LOC652128 PTGER4 ALDH1A1 FABP4 LOC652745 PTGIS ANK2FAM107A LRIG1 PTRF ANK3 FAM129A LRRC19 QKI ANKRD25 FAM46C MAB21L2 RAB27AANPEP FBLN1 MAFB RAB31 ANTXR1 FCGBP MAG1 RBMS1 AOC3 FGFR2 MALL RDX AP1S2FHL1 MAOA RELL1 APOE FILIP1L MAP1B RGS1 AQP1 FKBP5 MEIS1 RGS2 AQP8 FLNAMEP1A RGS5 ARL14 FNBP1 METTL7A SCARA5 ATP2B4 FOSB MFSD4 SCNN1B ATP8A1FOXF1 MGC14376 SDC2 AXL FOXF2 MIER3 SDCBP2 BCHE FOXP2 MLPH SDPR BEST2FXYD6 MMP2 SELENBP1 C10orf56 GALNAC4S- MPEG1 SELM C10orf99 6ST MPEG1SGCE C15orf48 GAS1 MRC1 SGK C1orf115 GCNT2 MRGPRF SI C20orf118 GCNT3MS4A12 SLC20A1 C2orf40 GJA1 MS4A4A SLC26A2 C4orf34 GNG2 MS4A7 SLC26A3C6orf105 GPA33 MSN SLC4A4 C6orf204 GPM6B MSRB3 SLITRK6 C7 GUCY1A3 MT1ASMOC2 C9orf19 HBA1 MT1E SMTN CA1 HBA2 MT1F SORBS1 CA2 HBB MT1G SRI CA4HCLS1 MT1H SRPX CALD1 HHLA2 MT1M ST6GALNAC1 CALM1 HIGD1A MT1X STMN2CAPN9 HLA-C MT2A STOM CAV1 HLA-DPA1 MUC12 SULT1A1 CCDC80 HLA-DPB1 MUCDHLSYNPO2 CCL28 HLA-DQA1 MXD1 TAGLN CD14 HLA-DRB1 MYL9 TBC1D9 CD163 HMGCS2MYLK TCEAL7 CD36 HPGD NEXN TCF21 CDKN2B HSD11B2 NID1 TGEB1I1 CEACAM1HSD17B2 NR3C1 TMEM47 CEACAM7 HSPA2 NR3C2 TNS1 CES2 HSPB6 OSTbetaTP53INP2 CFL2 HSPB8 P2RY1 TPM2 CHGA ID1 P2RY14 TRPM6 CITED2 IDH3A PAG1TSC22D3 CKB IGHA1 PALLD TSPAN1 CLCA1 IGHM PALM2- TSPAN7 CLCA4 IGKV1D-13AKAP2 TTRAP CLDN8 IGL@ PAPSS2 TUBB6 CLIC5 IGLJ3 PBLD TYROBP CMBL IL1R2PCK1 UGDH CNN1 IQGAP2 PDCD4 UGP2 CNTN3 ITLN1 PDE9A UGT1A1 COL4A2 ITM2APDGFRA UGT1A3 COL6A2 ITM2C PDK4 UGT1A6 COX7A1 KCNMA1 PDLIM3 UGT1A8 CRYABKCNMB1 PGM5 UGT1A9 CTSE KCTD12 PIGR UGT2A3 CYP3A5 KIAA0828 PKIB UGT2B15CYP3A5P2 KIAA1324 PLAC8 UGT2B17 DDR2 KLF4 PLCE1 VIM DES KLHL5 PLEKHC1VSIG2 DMN KRT20 PLN WDR51B DNASE1L3 L1TD1 PLOD2 WWTR1 DSCR1 LGALS1 PMP22XDH DUSP1 LGALS2 PNMA1 XLKD1 DUSP5 LIFR POU2AF1 ZSCAN18 EDG2 LMOD1PPAP2A LOC253012 PPAP2B

Reference to “nucleic acid molecule” should be understood as a referenceto both deoxyribonucleic acid molecules and ribonucleic acid moleculesand fragments thereof. The present invention therefore extends to bothdirectly screening for mRNA levels in a biological sample or screeningfor the complementary cDNA which has been reverse-transcribed from anmRNA population of interest. It is well within the skill of the personof skill in the art to design methodology directed to screening foreither DNA or RNA. As detailed above, the method of the presentinvention also extends to screening for the protein product translatedfrom the subject mRNA or the genomic DNA itself.

In one preferred embodiment, the level of gene expression is measured byreference to genes which encode a protein product and, moreparticularly, said level of expression is measured at the protein level.Accordingly, to the extent that the present invention is directed toscreening for markers which are detailed in the preceding table, saidscreening is preferably directed to the encoded protein.

In another particularly preferred embodiment, said gene expression isassessed by analysing genomic DNA methylation. In another embodiment,expression is assessed by the association of DNA with chromatin proteinscarrying repressive modifications, for example, methylation of lysines 9or 27 of histone H3.

As detailed hereinbefore, it should be understood that although thepresent invention is exemplified with respect to the detection ofexpressed nucleic acid molecules (e.g. mRNA), it also encompassesmethods of detection based on screening for the protein product of thesubject genes. The present invention should also be understood toencompass methods of detection based on identifying both proteins and/ornucleic acid molecules in one or more biological samples. This may be ofparticular significance to the extent that some of the neoplasticmarkers of interest may correspond to genes or gene fragments which donot encode a protein product. Accordingly, to the extent that thisoccurs it would not be possible to test for a protein and the subjectmarker would have to be assessed on the basis of transcriptionexpression profiles or changes to genomic DNA.

The term “protein” should be understood to encompass peptides,polypeptides and proteins (including protein fragments). The protein maybe glycosylated or unglycosylated and/or may contain a range of othermolecules fused, linked, bound or otherwise associated to the proteinsuch as amino acids, lipids, carbohydrates or other peptides,polypeptides or proteins. Reference herein to a “protein” includes aprotein comprising a sequence of amino acids as well as a proteinassociated with other molecules such as amino acids, lipids,carbohydrates or other peptides, polypeptides or proteins.

The proteins encoded by the neoplastic markers of the present inventionmay be in multimeric form meaning that two or more molecules areassociated together. Where the same protein molecules are associatedtogether, the complex is a homomultimer. An example of a homomultimer isa homodimer. Where at least one marker protein is associated with atleast one non-marker protein, then the complex is a heteromultimer suchas a heterodimer.

Reference to a “fragment” should be understood as a reference to aportion of the subject nucleic acid molecule or protein. This isparticularly relevant with respect to screening for modulated RNA levelsin stool samples since the subject RNA is likely to have been degradedor otherwise fragmented due to the environment of the gut. One maytherefore actually be detecting fragments of the subject RNA molecule,which fragments are identified by virtue of the use of a suitablyspecific probe.

Reference to the “onset” of a neoplasm, such as adenoma oradenocarcinoma, should be understood as a reference to one or more cellsof that individual exhibiting dysplasia. In this regard, the adenoma oradenocarcinoma may be well developed in that a mass of dysplastic cellshas developed. Alternatively, the adenoma or adenocarcinoma may be at avery early stage in that only relatively few abnormal cell divisionshave occurred at the time of diagnosis. The present invention alsoextends to the assessment of an individual's predisposition to thedevelopment of a neoplasm, such as an adenoma or adenocarcinoma. Withoutlimiting the present invention in any way, changed levels of theneoplastic markers may be indicative of that individual's predispositionto developing a neoplasia, such as the future development of an adenomaor adenocarcinoma or another adenoma or adenocarcinoma.

In yet another related aspect of the present invention, markers havebeen identified which enable the characterisation of neoplastic tissueof the large intestine in terms of whether it is an adenoma or a cancer.This development now provides a simple yet accurate means ofcharacterising tissue using means other than the traditional methodswhich are currently utilised.

According to this aspect of the present invention, there is provided amethod of characterising a neoplastic cell or cellular population, whichcell or cellular population is derived from the large intestine of anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

200600_at 204006_s_at 213428_s_at 200665_s_at 204051_s_at 213524_s_at200832_s_at 204122_at 213869_x_at 200974_at 204320_at 213905_x_at200986_at 204475_at 214247_s_at 201058_s_at 204620_s_at 215049_x_at201069_at 205479_s_at 215076_s_at 201105_at 205547_s_at 215646_s_at201141_at 205828_at 216442_x_at 201147_s_at 207173_x_at 217430_x_at201150_s_at 207191_s_at 217762_s_at 201162_at 208747_s_at 217763_s_at201163_s_at 208782_at 217764_s_at 201185_at 208788_at 218468_s_at201261_x_at 208850_s_at 218469_at 201289_at 208851_s_at 218559_s_at201426_s_at 209101_at 218638_s_at 201438_at 209156_s_at 219087_at201616_s_at 209218_at 221011_s_at 201645_at 209395_at 221729_at201667_at 209396_s_at 221730_at 201744_s_at 209596_at 221731_x_at201792_at 209875_s_at 37892_at 201842_s_at 209955_s_at 223122_s_at201852_x_at 210095_s_at 223235_s_at 201859_at 210495_x_at 224560_at201893_x_at 210511_s_at 224694_at 202237_at 210764_s_at 224724_at202238_s_at 210809_s_at 225664_at 202283_at 211161_s_at 225681_at202291_s_at 211571_s_at 225710_at 202310_s_at 211719_x_at 225799_at202311_s_at 211813_x_at 226237_at 202403_s_at 211896_s_at 226311_at202404_s_at 211959_at 226694_at 202450_s_at 211964_at 226777_at202620_s_at 211966_at 226930_at 202766_s_at 211980_at 227099_s_at202859_x_at 211981_at 227140_at 202878_s_at 212077_at 227566_at202917_s_at 212344_at 229218_at 202998_s_at 212353_at 229802_at203083_at 212354_at 231579_s_at 203325_s_at 212464_s_at 231766_s_at203382_s_at 212488_at 231879_at 203477_at 212489_at 232458_at 203570_at212667_at 233555_s_at 203645_s_at 213125_at 234994_at; and/or203878_s_at

-   -   (ii)

COL1A2 LGALS1 SRGN CTHRC1 ELOVL5 LBH FN1 MGP CTGF POSTN MMP2 TNC SPP1LOXL2 G0S2 MMP1 MYL9 SQLE SPARC DCN EFEMP1 LUM CALD1 APOE GREM1 FBN1 MSNIL8 MMP3 IGFBP3 IGFBP5 IGFBP7 SERPINF1 SFRP2 FSTL1 ISLR SULF1 COL4A2 HNTASPN VCAN COL5A1 COL6A3 SMOC2 OLFML2B COL8A1 HTRA1 KIAA1913 COL12A1CYR61 PALM2-AKAP2 COL5A2 FAP SERPING1 CDH11 VIM TYROBP THBS2 TIMP2 ACTA2COL15A1 SCD COL3A1 COL11A1 TIMP3 PLOD2 S100A8 AEBP1 MMP11 FNDC1 GJA1CD163 SFRP4 NNMT FCGR3B INHBA COL1A1 PLAU COL6A2 SULF2 MAFB ANTXR1COL6A1 LOC541471 GPNMB SPON2 LOC387763 BGN CTSK CHI3L1 TAGLN MXRA5 THY1COL4A1 C1S LOXL1 RAB31 DKK3 CD93in said cell or cellular population wherein a lower level of expressionof the genes of group (i) and/or group (ii) relative to agastrointestinal cancer control level is indicative of an adenoma cellor a cell predisposed to the onset of an adenoma state.

In another aspect there is provided a method of characterising aneoplastic cell or cellular population, which cell or cellularpopulation is derived from the large intestine of an individual, saidmethod comprising assessing the level of expression of one or more genesor transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

200884_at 214234_s_at 226248_s_at 203240_at 214235_at 226302_at203963_at 214433_s_at 227676_at 204508_s_at 215125_s_at 227719_at204607_at 215867_x_at 227725_at 204811_s_at 217109_at 228232_s_at204895_x_at 217110_s_at 229070_at 204897_at 218211_s_at 231832_at205259_at 219543_at 232176_at 205765_at 219955_at 232481_s_at205927_s_at 221841_s_at 235976_at 208063_s_at 221874_at 236894_at208937_s_at 223969_s_at 237521_x_at 210107_at 223970_at 242601_at;and/or 213106_at

-   -   (ii)

CLCA1 CTSE ATP8B1 FCGBP C6orfl05 CACNA2D2 HMGCS2 CKB KLF4 RETNLB ATP8A1CYP3A5P2 L1TD1 MUC4 CAPN9 SLITRK6 UGT1A1 NR3C2 VSIG2 SELENBP1 PBLDLOC253012 PTGER4 CA12 ST6GALNAC1 MLPH WDR51B ID1 KIAA1324 FAM3D CYP3A5in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to a gastrointestinal adenoma control level is indicative of acancer or a cell predisposed to the onset of a cancerous state.

Preferably, said gastrointestinal tissue is colorectal tissue.

In one embodiment, said expression is assessed by screening for DNAchanges which impact on methylation, in particular hypermethylation. Inanother embodiment, expression is assessed by the association of DNAwith chromatin proteins carrying repressive modifications, for example,methylation of lysines 9 or 27 of histone H3.

Reference to an “adenoma control level” or “cancer control level” shouldbe understood as a reference to the level of said gene expression in apopulation of adenoma or cancer gastrointestinal cells, respectively. Asdiscussed hereinbefore in relation to “normal levels”, the subject levelmay be a discrete level or a range of levels. Accordingly, thedefinition of “adenoma control level” or “cancer control level” shouldbe understood to have a corresponding definition to “normal level”,albeit in the context of the expression of genes by a neoplasticpopulation of large intestine cells.

In terms of this aspect of the present invention, the subject analysisis performed on a population of neoplastic cells. These cells may bederived in any manner, such as sloughed off neoplastic cells which havebeen collected via an enema wash or from a gastrointestinal sample, suchas a stool sample. Alternatively, the subject cells may have beenobtained via a biopsy or other surgical technique.

Without limiting this aspect of the invention in any way, several of themarkers of this aspect of the present invention have been determined tobe expressed at particularly significant levels below those ofneoplastic cells. For example, decreased expression levels of 3 to 9fold have been observed in respect of the following markers which areindicative of gastrointestinal adenomas, when assessed by the methodherein exemplified.

Gene, genes or transcripts detected by Affymetrix Fold Decrease ProbeNo: Gene 9 202404_s_at COL1A2 8 225681_at CTHRC1 7 212464_s_at FN1210809_s_at POSTN 6 209875_s_at SPP1 5 221740_at MMP1 204475_at 4200665_s_at SPARC 201744_s_at LUM 218468_s_at GREM1 202859_x_at IL8211959_at IGFBP5 3 223122_s_at SFRP2 212353_at SULF1 219087_at ASPN201438_at COL6A3 226237_at COL8A1 225664_at COL12A1 221730_at COL5A2207173_x_at CDH11 203083_at THBS2 203477_at COL15A1 37892_at COL11A1202917_s_at S100A8 226930_at FNDC1 204051_s_at SFRP4 210511_s_at INHBA209156_s_at COL6A2 224694_at ANTXR1 201141_at GPNMB 213905_x_at BGN205547_s_at TAGLN

In another example, decreased expression levels of between 3 to 5 foldhave been observed in respect of the following markers which areindicative of gastrointestinal cancers, when assessed by the methodherein exemplified.

Gene, genes or transcripts detected by Affymetrix Fold Decrease ProbeNo: Gene 5 210107_at CLCA1 3 203240_at FCGBP 204607_at HMGCS2223969_s_at RETNLB 219955_at L1TD1 232481_s_at SLITRK6 228232_s_at VSIG2242601_at LOC253012 227725_at ST6GALNAC1

According to this embodiment, there is therefore provided a method ofcharacterising a neoplastic cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene or genes detected by Affymetrix probeset IDs:        202404_s_at, 212464_s_at, 210809_s_a, 22568 l_at; and/or    -   (ii) COL1A2, CTHRC1, FN1, POSTN        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or group (ii) relative to a gastrointestinal cancer control        level is indicative of an adenoma cell or a cell predisposed to        the onset of an adenoma state.

In another embodiment, there is provided a method of characterising aneoplastic cell or cellular population, which cell or cellularpopulation is derived from the large intestine of an individual, saidmethod comprising assessing the level of expression of one or more genesselected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

209875_s_at 227140_at 204475_at; and/or

-   -   (ii)

SPP1 MMP1in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to a gastrointestinal cancer control level is indicative of anadenoma cell or a cell predisposed to the onset of an adenoma state.

Preferably, said gastrointestinal tissue is colorectal tissue.

Still more preferably, said biological sample is a tissue sample.

In another preferred embodiment the present invention is directed to amethod of characterising a cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs:

200665_s_at 226237_at 226930_at 201744_s_at 225664_at 204051_s_at218468_s_at 221730_at 210511_s_at 202859_x_at 207173_x_at 209156_s_at211959_at 203083_at 224694_at 223122_s_at 203477_at 201141_at 212353_at37892_at 213905_x_at 219087_at 202917_s_at 205547_s_at 201438_at; and/or

-   -   (ii)

SPARC COL8A1 SFRP4 LUM COL12A1 INHBA GREM1 COL5A2 COL6A2 IL8 CDH11ANTXR1 IGFBP5 THBS2 GPNMB SFRP2 COL15A1 BGN SULF1 COL11A1 TAGLN ASPNS100A8 COL6A3 FNDC1in a biological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or (ii) relativeto a gastrointestinal cancer control level is indicative of an adenomaor a cell predisposed to the onset of an adenoma state.

In yet another preferred embodiment the present invention is directed toa method of characterising a cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 210107_at; and/or    -   (ii) CLCA1        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or (ii) relative to a gastrointestinal adenoma control level        is indicative of a cancer or a cell predisposed to the onset of        a cancerous state.

In still yet another preferred embodiment the present invention isdirected to a method of characterising a cell or cellular population,which cell or cellular population is derived from the large intestine ofan individual, said method comprising assessing the level of expressionof one or more genes or transcripts selected from:

-   -   (i) the gene, genes or transcripts detected by Affymetrix        probeset IDs: 203240_at, 204607_at, 223969_sat, 219955_at,        232481_s_at, 242601_at, 227725_at, 228232_s_at; and/or    -   (ii) FCGBP, HMGCS2, RETNLB, L1TD1, SLITRK6, VSIG2, LOC253012,        ST6GALNAC1        in a biological sample from said individual wherein a lower        level of expression of the genes or transcripts of group (i)        and/or (ii) relative to a gastrointestinal adenoma control level        is indicative of a cancer or a cell predisposed to the onset of        a cancerous state.

Preferably, said gastrointestinal tissue is colorectal tissue.

Even more preferably, said biological sample is a tissue sample.

In still another related aspect it has been determined that a subset ofthe markers of this aspect of the present invention are useful asqualitative markers of neoplastic tissue characterisation in that thesemarkers, if not detectable at levels substantially above backgroundlevels in neoplastic tissue are indicative of cancerous tissue.

According to this aspect, the present invention provides a method ofcharacterising a neoplastic cell or cellular population, which cell orcellular population is derived from the large intestine of anindividual, said method comprising assessing the level of expression ofone or more genes or transcripts selected from:

-   -   (i) the gene or genes detected by Affymetrix probeset

235976_at 236894_at 237521; and/or

-   -   (ii)

SLITRK6 L1TD1in a biological sample from said individual wherein expression of thegenes or transcripts of group (i) and/or (ii) at a level which is notsubstantially greater than background neoplastic tissue levels isindicative of a cancer or a cell predisposed to the onset of a cancerousstate.

Preferably, said gastrointestinal tissue is colorectal tissue.

Still more preferably, said biological sample is a tissue sample.

In a most preferred embodiment, the methods of the present invention arepreferably directed to screening for proteins encoded by the markers ofthe present invention or changes to DNA methylation of genomic DNA. Inanother embodiment, expression is assessed by the association of DNAwith chromatin proteins carrying repressive modifications, for example,methylation of lysines 9 or 27 of histone H3.

Although the preferred method is to detect the expression product or DNAchanges of the neoplastic markers for the purpose of diagnosingneoplasia development or predisposition thereto, the detection ofconverse changes in the levels of said markers may be desired undercertain circumstances, for example, to monitor the effectiveness oftherapeutic or prophylactic treatment directed to modulating aneoplastic condition, such as adenoma or adenocarcinoma development. Forexample, where reduced expression of the subject markers indicates thatan individual has developed a condition characterised by adenoma oradenocarcinoma development, for example, screening for an increase inthe levels of these markers subsequently to the onset of a therapeuticregime may be utilised to indicate reversal or other form of improvementof the subject individual's condition.

The method of the present invention is therefore useful as a one offtest or as an on-going monitor of those individuals thought to be atrisk of neoplasia development or as a monitor of the effectiveness oftherapeutic or prophylactic treatment regimes directed to inhibiting orotherwise slowing neoplasia development. In these situations, mappingthe modulation of neoplastic marker expression levels in any one or moreclasses of biological samples is a valuable indicator of the status ofan individual or the effectiveness of a therapeutic or prophylacticregime which is currently in use. Accordingly, the method of the presentinvention should be understood to extend to monitoring for increases ordecreases in marker expression levels in an individual relative to theirnormal level (as hereinbefore defined), background control levels,cancer levels, adenoma levels or relative to one or more earlier markerexpression levels determined from a biological sample of saidindividual.

Means of assessing the subject expressed neoplasm markers in abiological sample can be achieved by any suitable method, which would bewell known to the person of skill in the art. To this end, it would beappreciated that to the extent that one is examining either ahomogeneous cellular population (such as a tumour biopsy or a cellularpopulation which has been enriched from a heterogeneous startingpopulation) or a tissue section, one may utilise a wide range oftechniques such as in situ hybridisation, assessment of expressionprofiles by microassays, immunoassays and the like (hereinafterdescribed in more detail) to detect the absence of or downregulation ofthe level of expression of one or more markers of interest. However, tothe extent that one is screening a heterogenous cellular population or abodily fluid in which heterogeneous populations of cells are found, suchas a blood sample, the absence of or reduction in level of expression ofa particular marker may be undetectable due to the inherent expressionof the marker by non-neoplastic cells which are present in the sample.That is, a decrease in the level of expression of a subgroup of cellsmay not be detectable. In this situation, a more appropriate mechanismof detecting a reduction in a neoplastic subpopulation of the expressionlevels of one or more markers of the present invention is via indirectmeans, such as the detection of epigenetic changes.

Without limiting the present invention to any one theory or mode ofaction, during development gene expression is regulated by processesthat alter the availability of genes for expression in different celllineages without any alteration in gene sequence, and these states canbe inherited through a cell division—a process called epigeneticinheritance. Epigenetic inheritance is determined by a combination ofDNA methylation (modification of cytosine to give 5-methyl cytosine, 5meC) and by modifications of the histone chromosomal proteins thatpackage DNA. Thus methylation of DNA at CpG sites and modifications suchas deacetylation of histone H3 on lysine 9, and methylation on lysine 9or 27 are associated with inactive chromatin, while the converse stateof a lack of DNA methylation, acetylation of lysine 9 of histone H3 isassociated with open chromatin and active gene expression. In cancer,this epigenetic regulation of gene expression is frequently found to bedisrupted (Esteller & Herman, 2000; Jones & Baylin, 2002). Genes such astumour suppressor or metastasis suppressor genes are often found to besilenced by DNA methylation, while other genes may be hypomethylated andinappropriately expressed. Thus, among genes that show a decrease orloss of expression in cancer, this is often characterised by methylationof the promoter or regulatory region of the gene.

A variety of methods are available for detection of aberrantlymethylated DNA of a specific gene, even in the presence of a largeexcess of normal DNA (Clark 2007). Thus, loss of expression of a genewhich can be difficult to detect at the protein or RNA level except byimmunohistochemistry can often be detected in tumour samples and inbodily fluids of cancer patients by the presence of hypermethylated DNAof the gene's promoter. Similarly DNA hypomethylation may be used forthe detection of certain genes whose expression is elevated in cancer.Epigenetic alterations and chromatin changes in cancer are also evidentin the altered association of modified histones with specific genes(Esteller, 2007); for example repressed genes are often found associatedwith histone H3 that is deacetylated and methylated on lysine 9. The useof antibodies targeted to altered histones allows for the isolation ofDNA associated with particular chromatin states and its potential use incancer diagnosis.

Other methods of detecting changes to gene expression levels,particularly where the subject biological sample is not contaminatedwith high numbers of non-neoplastic cells, include but are not limitedto:

-   (i) In vivo detection.    -   Molecular Imaging may be used following administration of        imaging probes or reagents capable of disclosing altered        expression of the markers in the intestinal tissues.    -   Molecular imaging (Moore et al., BBA, 1402:239-249, 1988;        Weissleder et al., Nature Medicine 6:351-355, 2000) is the in        vivo imaging of molecular expression that correlates with the        macro-features currently visualized using “classical” diagnostic        imaging techniques such as X-Ray, computed tomography (CT), MRI,        Positron Emission Tomography (PET) or endoscopy.-   (ii) Detection of downregulation of RNA expression in the cells by    Fluorescent In Situ Hybridization (FISH), or in extracts from the    cells by technologies such as Quantitative Reverse Transcriptase    Polymerase Chain Reaction (QRTPCR) or Flow cytometric qualification    of competitive RT-PCR products (Wedemeyer et al., Clinical Chemistry    48:9 1398-1405, 2002).-   (iii) Assessment of expression profiles of RNA, for example by array    technologies (Alon et al., Proc. Natl. Acad. Sci. USA: 96,    6745-6750, June 1999).    -   A “microarray” is a linear or multi-dimensional allay of        preferably discrete regions, each having a defined area, formed        on the surface of a solid support. The density of the discrete        regions on a microarray is determined by the total numbers of        target polynucleotides to be detected on the surface of a single        solid phase support. As used herein, a DNA microarray is an        array of oligonucleotide probes placed onto a chip or other        surfaces used to amplify or clone target polynucleotides. Since        the position of each particular group of probes in the array is        known, the identities of the target polynucleotides can be        determined based on their binding to a particular position in        the microarray.    -   Recent developments in DNA microarray technology make it        possible to conduct a large scale assay of a plurality of target        nucleic acid molecules on a single solid phase support. U.S.        Pat. No. 5,837,832 (Chee et al.) and related patent applications        describe immobilizing an array of oligonucleotide probes for        hybridization and detection of specific nucleic acid sequences        in a sample. Target polynucleotides of interest isolated from a        tissue of interest are hybridized to the DNA chip and the        specific sequences detected based on the target polynucleotides'        preference and degree of hybridization at discrete probe        locations. One important use of arrays is in the analysis of        differential gene expression, where the profile of expression of        genes in different cells or tissues, often a tissue of interest        and a control tissue, is compared and any differences in gene        expression among the respective tissues are identified. Such        information is useful for the identification of the types of        genes expressed in a particular tissue type and diagnosis of        conditions based on the expression profile.    -   In one example, RNA from the sample of interest is subjected to        reverse transcription to obtain labelled cDNA. See U.S. Pat. No.        6,410,229 (Lockhart et al.) The cDNA is then hybridized to        oligonucleotides or cDNAs of known sequence arrayed on a chip or        other surface in a known order. In another example, the RNA is        isolated from a biological sample and hybridised to a chip on        which are anchored cDNA probes. The location of the        oligonucleotide to which the labelled cDNA hybridizes provides        sequence information on the cDNA, while the amount of labelled        hybridized RNA or cDNA provides an estimate of the relative        representation of the RNA or cDNA of interest. See Schena, et        al. Science 270:467-470 (1995). For example, use of a cDNA        microarray to analyze gene expression patterns in human cancer        is described by DeRisi, et al. (Nature Genetics 14:457-460        (1996)).    -   In a preferred embodiment, nucleic acid probes corresponding to        the subject nucleic acids are made. The nucleic acid probes        attached to the biochip are designed to be substantially        complementary to the nucleic acids of the biological sample such        that specific hybridization of the target sequence and the        probes of the present invention occurs. This complementarity        need not be perfect, in that there may be any number of base        pair mismatches that will interfere with hybridization between        the target sequence and the single stranded nucleic acids of the        present invention. It is expected that the overall homology of        the genes at the nucleotide level probably will be about 40% or        greater, probably about 60% or greater, and even more probably        about 80% or greater; and in addition that there will be        corresponding contiguous sequences of about 8-12 nucleotides or        longer. However, if the number of mutations is so great that no        hybridization can occur under even the least stringent of        hybridization conditions, the sequence is not a complementary        target sequence. Thus, by “substantially complementary” herein        is meant that the probes are sufficiently complementary to the        target sequences to hybridize under normal reaction conditions,        particularly high stringency conditions.    -   A nucleic acid probe is generally single stranded but can be        partly single and partly double stranded. The strandedness of        the probe is dictated by the structure, composition, and        properties of the target sequence. In general, the        oligonucleotide probes range from about 6, 8, 10, 12, 15, 20, 30        to about 100 bases long, with from about 10 to about 80 bases        being preferred, and from about 15 to about 40 bases being        particularly preferred. That is, generally entire genes are        rarely used as probes. In some embodiments, much longer nucleic        acids can be used, up to hundreds of bases. The probes are        sufficiently specific to hybridize to a complementary template        sequence under conditions known by those of skill in the art.        The number of mismatches between the probe's sequences and their        complementary template (target) sequences to which they        hybridize during hybridization generally do not exceed 15%,        usually do not exceed 10% and preferably do not exceed 5%,        as-determined by BLAST (default settings).    -   Oligonucleotide probes can include the naturally-occurring        heterocyclic bases normally found in nucleic acids (uracil,        cytosine, thymine, adenine and guanine), as well as modified        bases and base analogues. Any modified base or base analogue        compatible with hybridization of the probe to a target sequence        is useful in the practice of the invention. The sugar or        glycoside portion of the probe can comprise deoxyribose, ribose,        and/or modified forms of these sugars, such as, for example,        2′-O-alkyl ribose. In a preferred embodiment, the sugar moiety        is 2′-deoxyribose; however, any sugar moiety that is compatible        with the ability of the probe to hybridize to a target sequence        can be used.    -   In one embodiment, the nucleoside units of the probe are linked        by a phosphodiester backbone, as is well known in the art. In        additional embodiments, internucleotide linkages can include any        linkage known to one of skill in the art that is compatible with        specific hybridization of the probe including, but not limited        to phosphorothioate, methylphosphonate, sulfamate (e.g., U.S.        Pat. No. 5,470,967) and polyamide (i.e., peptide. nucleic        acids). Peptide nucleic acids are described in Nielsen et        al. (1991) Science 254: 1497-1500, U.S. Pat. No. 5,714,331, and        Nielsen (1999) Curr. Opin. Biotechnol. 10:71-75.    -   In certain embodiments, the probe can be a chimeric molecule;        i.e., can comprise more than one type of base or sugar subunit,        and/or the linkages can be of more than one type within the same        primer. The probe can comprise a moiety to facilitate        hybridization to its target sequence, as are known in the art,        for example, intercalators and/or minor groove binders.        Variations of the bases, sugars, and internucleoside backbone,        as well as the presence of any pendant group on the probe, will        be compatible with the ability of the probe to bind, in a        sequence-specific fashion, with its target sequence. A large        number of structural modifications, are possible within these        bounds. Advantageously, the probes according to the present        invention may have structural characteristics such that they        allow the signal amplification, such structural characteristics        being, for example, branched DNA probes as those described by        Urdea et al. (Nucleic Acids Symp. Ser., 24:197-200 (1991)) or in        the European Patent No. EP-0225,807. Moreover, synthetic methods        for preparing the various heterocyclic bases, sugars,        nucleosides and nucleotides that form the probe, and preparation        of oligonucleotides of specific predetermined sequence, are        well-developed and known in the art. A preferred method for        oligonucleotide synthesis incorporates the teaching of U.S. Pat.        No. 5,419,966.    -   Multiple probes may be designed for a particular target nucleic        acid to account for polymorphism and/or secondary structure in        the target nucleic acid, redundancy of data and the like. In        some embodiments, where more than one probe per sequence is        used, either overlapping probes or probes to different sections        of a single target gene are used. That is, two, three, four or        more probes, are used to build in a redundancy for a particular        target. The probes can be overlapping (i.e. have some sequence        in common), or are specific for distinct sequences of a gene.        When multiple target polynucleotides are to be detected        according to the present invention, each probe or probe group        corresponding to a particular target polynucleotide is situated        in a discrete area of the microarray.    -   Probes may be in solution, such as in wells or on the surface of        a micro-array, or attached to a solid support. Examples of solid        support materials that can be used include a plastic, a ceramic,        a metal, a resin, a gel and a membrane. Useful types of solid        supports include plates, beads, magnetic material, microbeads,        hybridization chips, membranes, crystals, ceramics and        self-assembling monolayers. One example comprises a        two-dimensional or three-dimensional matrix, such as a gel or        hybridization chip with multiple probe binding sites (Pevzner et        al., J. Biomol. Struc. & Dyn. 9:399-410, 1991; Maskos and        Southern, Nuc. Acids Res. 20:1679-84, 1992). Hybridization chips        can be used to construct very large probe arrays that are        subsequently hybridized with a target nucleic acid. Analysis of        the hybridization pattern of the chip can assist in the        identification of the target nucleotide sequence. Patterns can        be manually or computer analyzed, but it is clear that        positional sequencing by hybridization lends itself to computer        analysis and automation. In another example, one may use an        Affymetrix chip on a solid phase structural support in        combination with a fluorescent bead based approach. In yet        another example, one may utilise a cDNA microarray. In this        regard, the oligonucleotides described by Lockkart et al (i.e.        Affymetrix synthesis probes in situ on the solid phase) are        particularly preferred, that is, photolithography.    -   As will be appreciated by those in the art, nucleic acids can be        attached or immobilized to a solid support in a wide variety of        ways. By “immobilized” herein is meant the association or        binding between the nucleic acid probe and the solid support is        sufficient to be stable under the conditions of binding,        washing, analysis, and removal. The binding can be covalent or        non-covalent. By “non-covalent binding” and grammatical        equivalents herein is meant one or more of either electrostatic,        hydrophilic, and hydrophobic interactions. Included in        non-covalent binding is the covalent attachment of a molecule,        such as streptavidin, to the support and the non-covalent        binding of the biotinylated probe to the streptavidin. By        “covalent binding” and grammatical equivalents herein is meant        that the two moieties, the solid support and the probe, are        attached by at least one bond, including sigma bonds, pi bonds        and coordination bonds. Covalent bonds can be formed directly        between the probe and the solid support or can be formed by a        cross linker or by inclusion of a specific reactive group on        either the solid support or the probe or both molecules.        Immobilization may also involve a combination of covalent and        non-covalent interactions.    -   Nucleic acid probes may be attached to the solid support by        covalent binding such as by conjugation with a coupling agent or        by covalent or non-covalent binding such as electrostatic        interactions, hydrogen bonds or antibody-antigen coupling, or by        combinations thereof. Typical coupling agents include        biotin/avidin, biotin/streptavidin, Staphylococcus aureus        protein A/IgG antibody F_(c) fragment, and streptavidin/protein        A chimeras (T. Sano and C. R. Cantor, Bio/Technology 9:1378-81        (1991)), or derivatives or combinations of these agents. Nucleic        acids may be attached to the solid support by a photocleavable        bond, an electrostatic bond, a disulfide bond, a peptide bond, a        diester bond or a combination of these sorts of bonds. The array        may also be attached to the solid support by a selectively        releasable bond such as 4,4′-dimethoxytrityl or its derivative.        Derivatives which have been found to be useful include 3 or 4        [bis-(4-methoxyphenyl)]-methyl-benzoic acid, N-succinimidyl-3 or        4 [bis-(4-methoxyphenyl)]-methyl-benzoic acid, N-succinimidyl-3        or 4 [bis-(4-methoxyphenyl)]-hydroxymethyl-benzoic acid,        N-succinimidyl-3 or 4        [bis-(4-methoxyphenyl)]-chloromethyl-benzoic acid, and salts of        these acids.    -   In general, the probes are attached to the biochip in a wide        variety of ways, as will be appreciated by those in the art. As        described herein, the nucleic acids can either be synthesized        first, with subsequent attachment to the biochip, or can be        directly synthesized on the biochip.    -   The biochip comprises a suitable solid substrate. By “substrate”        or “solid support” or other grammatical equivalents herein is        meant any material that can be modified to contain discrete        individual sites appropriate for the attachment or association        of the nucleic acid probes and is amenable to at least one        detection method. The solid phase support of the present        invention can be of any solid materials and structures suitable        for supporting nucleotide hybridization and synthesis.        Preferably, the solid phase support comprises at least one        substantially rigid surface on which the primers can be        immobilized and the reverse transcriptase reaction performed.        The substrates with which the polynucleotide microarray elements        are stably associated and may be fabricated from a variety of        materials, including plastics, ceramics, metals, acrylamide,        cellulose, nitrocellulose, glass, polystyrene, polyethylene        vinyl acetate, polypropylene, polymethacrylate, polyethylene,        polyethylene oxide, polysilicates, polycarbonates, Teflon,        fluorocarbons, nylon, silicon rubber, polyanhydrides,        polyglycolic acid, polylactic acid, polyorthoesters,        polypropylfumerate, collagen, glycosaminoglycans, and polyamino        acids. Substrates may be two-dimensional or three-dimensional in        form, such as gels, membranes, thin films, glasses, plates,        cylinders, beads, magnetic beads, optical fibers, woven fibers,        etc. A preferred form of array is a three-dimensional array. A        preferred three-dimensional array is a collection of tagged        beads. Each tagged bead has different primers attached to it.        Tags are detectable by signalling means such as color (Luminex,        Illumina) and electromagnetic field (Pharmaseq) and signals on        tagged beads can even be remotely detected (e.g., using optical        fibers). The size of the solid support can be any of the        standard microarray sizes, useful for DNA microarray technology,        and the size may be tailored to fit the particular machine being        used to conduct a reaction of the invention. In general, the        substrates allow optical detection and do not appreciably        fluoresce.    -   In one embodiment, the surface of the biochip and the probe may        be derivatized with chemical functional groups for subsequent        attachment of the two. Thus, for example, the biochip is        derivatized with a chemical functional group including, but not        limited to, amino groups, carboxy groups; oxo groups and thiol        groups, with amino groups being particularly preferred. Using        these functional groups, the probes can be attached using        functional groups on the probes. For example, nucleic acids        containing amino groups can be attached to surfaces comprising        amino groups, for example using linkers as are known in the art;        for example, homo- or hetero-bifunctional linkers as are well        known. In addition, in some cases, additional linkers, such as        alkyl groups (including substituted and heteroalkyl groups) may        be used.    -   In this embodiment, the oligonucleotides are synthesized as is        known in the art, and then attached to the surface of the solid        support. As will be appreciated by those skilled in the art,        either the 5′ or 3′ terminus may be attached to the solid        support, or attachment may be via an internal nucleoside. In an        additional embodiment, the immobilization to the solid support        may be very strong, yet non-covalent. For example, biotinylated        oligonucleotides can be made, which bind to surfaces covalently        coated with streptavidin, resulting in attachment.    -   The arrays may be produced according to any convenient        methodology, such as preforming the polynucleotide microarray        elements and then stably associating them with the surface.        Alternatively, the oligonucleotides may be synthesized on the        surface, as is known in the art. A number of different array        configurations and methods for their production are known to        those of skill in the art and disclosed in WO 95/25116 and WO        95/35505 (photolithographic techniques), U.S. Pat. No. 5,445,934        (in situ synthesis by photolithography), U.S. Pat. No. 5,384,261        (in situ synthesis by mechanically directed flow paths); and        U.S. Pat. No. 5,700,637 (synthesis by spotting, printing or        coupling); the disclosure of which are herein incorporated in        their entirety by reference. Another method for coupling DNA to        beads uses specific ligands attached to the end of the DNA to        link to ligand-binding molecules attached to a bead. Possible        ligand-binding partner pairs include biotin-avidin/streptavidin,        or various antibody/antigen pairs such as        digoxygenin-antidigoxygenin antibody (Smith et al., Science        258:1122-1126 (1992)). Covalent chemical attachment of DNA to        the support can be accomplished by using standard coupling        agents to link the 5′-phosphate on the DNA to coated        microspheres through a phosphoamidate bond. Methods for        immobilization of oligonucleotides to solid-state substrates are        well established. See Pease et al., Proc. Natl. Acad. Sci. USA        91(11):5022-5026 (1994). A preferred method of attaching        oligonucleotides to solid-state substrates is described by Guo        et al., Nucleic Acids Res. 22:5456-5465 (1994). Immobilization        can be accomplished either by in situ DNA synthesis (Maskos and        Southern, supra) or by covalent attachment of chemically        synthesized oligonucleotides (Guo et al., supra) in combination        with robotic arraying technologies.    -   In addition to the solid-phase technology represented by biochip        arrays, gene expression can also be quantified using        liquid-phase arrays. One such system is kinetic polymerase chain        reaction (PCR). Kinetic PCR allows for the simultaneous        amplification and quantification of specific nucleic acid        sequences. The specificity is derived from synthetic        oligonucleotide primers designed to preferentially adhere to        single-stranded nucleic acid sequences bracketing the target        site. This pair of oligonucleotide primers form specific,        non-covalently bound complexes on each strand of the target        sequence. These complexes facilitate in vitro transcription of        double-stranded DNA in opposite orientations. Temperature        cycling of the reaction mixture creates a continuous cycle of        primer binding, transcription, and re-melting of the nucleic        acid to individual strands. The result is an exponential        increase of the target dsDNA product. This product can be        quantified in real time either through the use of an        intercalating dye or a sequence specific probe. SYBR(r) Green 1,        is an example of an intercalating dye, that preferentially binds        to dsDNA resulting in a concomitant increase in the fluorescent        signal. Sequence specific probes, such as used with TaqMan        technology, consist of a fluorochrome and a quenching molecule        covalently bound to opposite ends of an oligonucleotide. The        probe is designed to selectively bind the target DNA sequence        between the two primers. When the DNA strands are synthesized        during the PCR reaction, the fluorochrome is cleaved from the        probe by the exonuclease activity of the polymerase resulting in        signal dequenching. The probe signalling method can be more        specific than the intercalating dye method, but in each case,        signal strength is proportional to the dsDNA product produced.        Each type of quantification method can be used in multi-well        liquid phase arrays with each well representing primers and/or        probes specific to nucleic acid sequences of interest. When used        with messenger RNA preparations of tissues or cell lines, an        array of probe/primer reactions can simultaneously quantify the        expression of multiple gene products of interest. See Germer et        al., Genome Res. 10:258-266 (2000); Heid et al., Genome Res.        6:986-994 (1996).-   (iv) Measurement of altered neoplastic marker protein levels in cell    extracts, for example by immunoassay.    -   Testing for proteinaceous neoplastic marker expression product        in a biological sample can be performed by any one of a number        of suitable methods which are well known to those skilled in the        art. Examples of suitable methods include, but are not limited        to, antibody screening of tissue sections, biopsy specimens or        bodily fluid samples.    -   To the extent that antibody based methods of diagnosis are used,        the presence of the marker protein may be determined in a number        of ways such as by Western blotting, ELISA or flow cytometry        procedures. These, of course, include both single-site and        two-site or “sandwich” assays of the non-competitive types, as        well as in the traditional competitive binding assays. These        assays also include direct binding of a labelled antibody to a        target.    -   Sandwich assays are a useful and commonly used assay. A number        of variations of the sandwich assay technique exist, and all are        intended to be encompassed by the present invention. Briefly, in        a typical forward assay, an unlabelled antibody is immobilized        on a solid substrate and the sample to be tested brought into        contact with the bound molecule. After a suitable period of        incubation, for a period of time sufficient to allow formation        of an antibody-antigen complex, a second antibody specific to        the antigen, labelled with a reporter molecule capable of        producing a detectable signal is then added and incubated,        allowing time sufficient for the formation of another complex of        antibody-antigen-labelled antibody. Any unreacted material is        washed away, and the presence of the antigen is determined by        observation of a signal produced by the reporter molecule. The        results may either be qualitative, by simple observation of the        visible signal, or may be quantitated by comparing with a        control sample. Variations on the forward assay include a        simultaneous assay, in which both sample and labelled antibody        are added simultaneously to the bound antibody. These techniques        are well known to those skilled in the art, including any minor        variations as will be readily apparent.    -   In the typical forward sandwich assay, a first antibody having        specificity for the marker or antigenic parts thereof, is either        covalently or passively bound to a solid surface. The solid        surface is typically glass or a polymer, the most commonly used        polymers being cellulose, polyacrylamide, nylon, polystyrene,        polyvinyl chloride or polypropylene. The solid supports may be        in the form of tubes, beads, discs of microplates, or any other        surface suitable for conducting an immunoassay. The binding        processes are well-known in the art and generally consist of        cross-linking, covalently binding or physically adsorbing, the        polymer-antibody complex is washed in preparation for the test        sample. An aliquot of the sample to be tested is then added to        the solid phase complex and incubated for a period of time        sufficient (e.g. 2-40 minutes) and under suitable conditions        (e.g. 25° C.) to allow binding of any subunit present in the        antibody. Following the incubation period, the antibody subunit        solid phase is washed and dried and incubated with a second        antibody specific for a portion of the antigen. The second        antibody is linked to a reporter molecule which is used to        indicate the binding of the second antibody to the antigen.    -   An alternative method involves immobilizing the target molecules        in the biological sample and then exposing the immobilized        target to specific antibody which may or may not be labelled        with a reporter molecule. Depending on the amount of target and        the strength of the reporter molecule signal, a bound target may        be detectable by direct labelling with the antibody.        Alternatively, a second labelled antibody, specific to the first        antibody is exposed to the target-first antibody complex to form        a target-first antibody-second antibody tertiary complex. The        complex is detected by the signal emitted by the reporter        molecule.    -   By “reporter molecule” as used in the present specification, is        meant a molecule which, by its chemical nature, provides an        analytically identifiable signal which allows the detection of        antigen-bound antibody. Detection may be either qualitative or        quantitative. The most commonly used reporter molecules in this        type of assay are either enzymes, fluorophores or radionuclide        containing molecules (i.e. radioisotopes) and chemiluminescent        molecules.    -   In the case of an enzyme immunoassay, an enzyme is conjugated to        the second antibody, generally by means of glutaraldehyde or        periodate. As will be readily recognized, however, a wide        variety of different conjugation techniques exist, which are        readily available to the skilled artisan. Commonly used enzymes        include horseradish peroxidase, glucose oxidase,        beta-galactosidase and alkaline phosphatase, amongst others. The        substrates to be used with the specific enzymes are generally        chosen for the production, upon hydrolysis by the corresponding        enzyme, of a detectable color change. Examples of suitable        enzymes include alkaline phosphatase and peroxidase. It is also        possible to employ fluorogenic substrates, which yield a        fluorescent product rather than the chromogenic substrates noted        above. In all cases, the enzyme-labelled antibody is added to        the first antibody hapten complex, allowed to bind, and then the        excess reagent is washed away. A solution containing the        appropriate substrate is then added to the complex of        antibody-antigen-antibody. The substrate will react with the        enzyme linked to the second antibody, giving a qualitative        visual signal, which may be further quantitated, usually        spectrophotometrically, to give an indication of the amount of        antigen which was present in the sample. “Reporter molecule”        also extends to use of cell agglutination or inhibition of        agglutination such as red blood cells on latex beads, and the        like.    -   Alternately, fluorescent compounds, such as fluorecein and        rhodamine, may be chemically coupled to antibodies without        altering their binding capacity. When activated by illumination        with light of a particular wavelength, the fluorochrome-labelled        antibody adsorbs the light energy, inducing a state to        excitability in the molecule, followed by emission of the light        at a characteristic color visually detectable with a light        microscope. As in the ETA, the fluorescent labelled antibody is        allowed to bind to the first antibody-hapten complex. After        washing off the unbound reagent, the remaining tertiary complex        is then exposed to the light of the appropriate wavelength the        fluorescence observed indicates the presence of the hapten of        interest. Immunofluorescence and ETA techniques are both very        well established in the art and are particularly preferred for        the present method. However, other reporter molecules, such as        radioisotope, chemiluminescent or bioluminescent molecules, may        also be employed.-   (v) Determining altered expression of protein neoplastic markers on    the cell surface, for example by immunohistochemistry.-   (vi) Determining altered protein expression based on any suitable    functional test, enzymatic test or immunological test in addition to    those detailed in points (iv) and (v) above.

A person of ordinary skill in the art could determine, as a matter ofroutine procedure, the appropriateness of applying a given method to aparticular type of biological sample.

Without limiting the present invention in any way, and as detailedabove, gene expression levels can be measured by a variety of methodsknown in the art. For example, gene transcription or translationproducts can be measured. Gene transcription products, i.e., RNA, can bemeasured, for example, by hybridization assays, run-off assays.,Northern blots, or other methods known in the art.

Hybridization assays generally involve the use of oligonucleotide probesthat hybridize to the single-stranded RNA transcription products. Thus,the oligonucleotide probes are complementary to the transcribed RNAexpression product. Typically, a sequence-specific probe can be directedto hybridize to RNA or cDNA. A “nucleic acid probe”, as used herein, canbe a DNA probe or an RNA probe that hybridizes to a complementarysequence. One of skill in the art would know how to design such a probesuch that sequence specific hybridization will occur. One of skill inthe art will further know how to quantify the amount of sequencespecific hybridization as a measure of the amount of gene expression forthe gene was transcribed to produce the specific RNA.

The hybridization sample is maintained under conditions that aresufficient to allow specific hybridization of the nucleic acid probe toa specific gene expression product. “Specific hybridization”, as usedherein, indicates near exact hybridization (e.g., with few if anymismatches). Specific hybridization can be performed under highstringency conditions or moderate stringency conditions. In oneembodiment, the hybridization conditions for specific hybridization arehigh stringency. For example, certain high stringency conditions can beused to distinguish perfectly complementary nucleic acids from those ofless complementarity. “High stringency conditions”, “moderate stringencyconditions” and “low stringency conditions” for nucleic acidhybridizations are explained on pages 2.10.1-2.10.16 and pages6.3.1-6.3.6 in Current Protocols in Molecular Biology (Ausubel, F. etal., “Current Protocols in Molecular Biology”, John Wiley & Sons,(1998), the entire teachings of which are incorporated by referenceherein). The exact conditions that determine the stringency ofhybridization depend not only on ionic strength (e.g., 0.2.times.SSC,0.1.times.SSC), temperature (e.g., room temperature, 42° C., 68° C.) andthe concentration of destabilizing agents such as formamide ordenaturing agents such as SDS, but also on factors such as the length ofthe nucleic acid sequence, base composition, percent mismatch betweenhybridizing sequences and the frequency of occurrence of subsets of thatsequence within other non-identical sequences. Thus, equivalentconditions can be determined by varying one or more of these parameterswhile maintaining a similar degree of identity or similarity between thetwo nucleic acid molecules. Typically, conditions are used such thatsequences at least about 60%, at least about 70%, at least about 80%, atleast about 90% or at least about 95% or more identical to each otherremain hybridized to one another. By varying hybridization conditionsfrom a level of stringency at which no hybridization occurs to a levelat which hybridization is first observed, conditions that will allow agiven sequence to hybridize (e.g., selectively) with the mostcomplementary sequences in the sample can be determined.

Exemplary conditions that describe the determination of wash conditionsfor moderate or low stringency conditions are described in Kraus, M. andAaronson, S., 1991. Methods Enzymol., 200:546-556; and in, Ausubel etal., Current Protocols in Molecular Biology, John Wiley & Sons, (1998).Washing is the step in which conditions are usually set so as todetermine a minimum level of complementarity of the hybrids. Generally,starting from the lowest temperature at which only homologoushybridization occurs, each ° C. by which the final wash temperature isreduced (holding SSC concentration constant) allows an increase by 1% inthe maximum mismatch percentage among the sequences that hybridize.Generally, doubling the concentration of SSC results in an increase inT_(m) of about 17° C. Using these guidelines, the wash temperature canbe determined empirically for high, moderate or low stringency,depending on the level of mismatch sought. For example, a low stringencywash can comprise washing in a solution containing 0.2.times.SSC/0.1%SDS for 10 minutes at room temperature; a moderate stringency wash cancomprise washing in a pre-warmed solution (42° C.) solution containing0.2.times.SSC/0.1% SDS for 15 minutes at 42° C.; and a high stringencywash can comprise washing in pre-warmed (68° C.) solution containing0.1.times.SSC/0.1% SDS for 15 minutes at 68° C. Furthermore, washes canbe performed repeatedly or sequentially to obtain a desired result asknown in the art. Equivalent conditions can be determined by varying oneor more of the parameters given as an example, as known in the art,while maintaining a similar degree of complementarity between the targetnucleic acid molecule and the primer or probe used (e.g., the sequenceto be hybridized).

A related aspect of the present invention provides a molecular array,which array comprises a plurality of

-   (i) nucleic acid molecules comprising a nucleotide sequence    corresponding to any one or more of the neoplastic marker genes    hereinbefore described or a sequence exhibiting at least 80%    identity thereto or a functional derivative, fragment, variant or    homologue of said nucleic acid molecule; or-   (ii) nucleic acid molecules comprising a nucleotide sequence capable    of hybridising to any one or more of the sequences of (i) under    medium stringency conditions or a functional derivative, fragment,    variant or homologue of said nucleic acid molecule; or-   (iii) nucleic acid probes or oligonucleotides comprising a    nucleotide sequence capable of hybridising to any one or more of the    sequences of (i) under medium stringency conditions or a functional    derivative, fragment, variant or homologue of said nucleic acid    molecule; or-   (iv) probes capable of binding to any one or more of the proteins    encoded by the nucleic acid molecules of (i) or a derivative,    fragment or, homologue thereof    wherein the level of expression of said marker genes of (i) or    proteins of (iv) is indicative of the neoplastic state of a cell or    cellular subpopulation derived from the large intestine.

Preferably, said percent identity is at least 85%, 90%, 91%, 92%, 93%,94%, 95%, 96%, 97%, 98% or 99%.

Low stringency includes and encompasses from at least about 1% v/v to atleast about 15% v/v formamide and from at least about 1M to at leastabout 2M salt for hybridisation, and at least about 1M to at least about2M salt for washing conditions. Alternative stringency conditions may beapplied where necessary, such as medium stringency, which includes andencompasses from at least about 16% v/v at least about 30% v/v formamideand from at least about 0.5M to at least about 0.9M salt forhybridisation, and at least about 0.5M to at least about 0.9M salt forwashing conditions, or high stringency, which includes and encompassesfrom at least about 31% v/v to at least about 50% v/v formamide and fromat least about 0.01M to at least about 0.15M salt for hybridisation, andat least about 0.01M to at least about 0.15M salt for washingconditions. In general, washing is carried out at T_(m)=69.3+0.41 (G+C)% [19]=−12° C. However, the T_(m) of a duplex DNA decreases by 1° C.with every increase of 1% in the number of mismatched based pairs(Bonner et al (1973) J. Mol. Biol. 81:123).

Preferably, the subject probes are designed to bind to the nucleic acidor protein to which they are directed with a level of specificity whichminimises the incidence of non-specific reactivity. However, it would beappreciated that it may not be possible to eliminate all potentialcross-reactivity or non-specific reactivity, this being an inherentlimitation of any probe based system.

In terms of the probes which are used to detect the subject proteins,they may take any suitable form including antibodies and aptamers.

A library or array of nucleic acid or protein probes provides rich andhighly valuable information. Further, two or more arrays or profiles(information obtained from use of an array) of such sequences are usefultools for comparing a test set of results with a reference, such asanother sample or stored calibrator. In using an array, individualprobes typically are immobilized at separate locations and allowed toreact for binding reactions. Primers associated with assembled sets ofmarkers are useful for either preparing libraries of sequences ordirectly detecting markers from other biological samples.

A library (or array, when referring to physically separated nucleicacids corresponding to at least some sequences in a library) of genemarkers exhibits highly desirable properties. These properties areassociated with specific conditions, and may be characterized asregulatory profiles. A profile, as termed here refers to a set ofmembers that provides diagnostic information of the tissue from whichthe markers were originally derived. A profile in many instancescomprises a series of spots on an array made from deposited sequences.

A characteristic patient profile is generally prepared by use of anarray. An array profile may be compared with one or more other arrayprofiles or other reference profiles. The comparative results canprovide rich information pertaining to disease states, developmentalstate, receptiveness to therapy and other information about the patient.

Another aspect of the present invention provides a diagnostic kit forassaying biological samples comprising an agent for detecting one ormore neoplastic marker reagents useful for facilitating the detection bythe agent in the first compartment. Further means may also be included,for example, to receive a biological sample. The agent may be anysuitable detecting molecule.

The present invention is further described by the following non-limitingexamples:

Example 1 Methods and Materials Affymetrix GeneChip Data

Gene expression profiling data and accompanying clinical data waspurchased from GeneLogic Inc (Gaithersburg, Md. USA). For each tissueanalysed, oligonucleotide microarray data for 44,928 probesets(Affymetrix HGU133A & HGU133B, combined), experimental and clinicaldescriptors, and digitally archived microscopy images of histologicalpreparations were received. A quality control analysis was performed toremove arrays not meeting essential quality control measures as definedby the manufacturer.

Transcript expression levels were calculated by both Microarray Suite(MAS) 5.0 (Affymetrix) and the Robust Multichip Average (RMA)normalization techniques (Affymetrix. GeneChip expression data analysisfundamentals. Affymetrix, Santa Clara, Calif. USA, 2001; Hubbell et al.Bioinformatics, 18:1585-1592, 2002; Irizarry et al. Nucleic AcidResearch, 31, 2003) MAS normalized data was used for performing standardquality control routines and the final data set was normalized with RMAfor all subsequent analyses.

Univariate Differential Expression

Differentially expressed gene transcripts were identified using amoderated t-test implemented in the Emma library downloaded from theBioconductor repository for R. (G. K. Smyth. Statistical Applications inGenetics and Molecular Biology, 3(1):Article 3, 2004; G K Smyth.Bioinformatics and Computational Biology Solutions using R andBioconductor. Springer, New York, 2005). Significance estimates(p-values) were corrected to adjust for multiple hypothesis testingusing the Bonferonni correction.

Tissue Specific Expression Patterns

To construct a filter for hypothetically ‘turned off’ gene expressionthe mean expression level for all 44,928 probesets across the full rangeof 454 tissues was first estimated. To estimate an expression on/offthreshold, the 44,928 mean values were ranked and the expression valueequivalent to the 30th percentile across the dataset calculated. Thisarbitrary threshold was chosen because it was theorized that themajority of transcripts (and presumably more than 30%) in a givenspecimen should be transcriptionally silenced. Thus this thresholdrepresents a conservative upper bound for what is estimated asnon-specific, or background, signal.

Gene Symbol Annotations

To map Affymetrix probeset names to official gene symbols the annotationmetadata available from Bioconductor was used. Hgu133plus2 libraryversion 1.16.0, which was assembled using Entrez Gene data downloaded on15 Mar. 2007, was used.

Estimates of Performance Characteristics

Diagnostic utility for each table of markers shown herein was estimatedincluding: sensitivity, specificity, positive predictive value, negativepredictive value, likelihood ratio positive, likelihood ratio negative.These estimates were calculated in the same data used to discover themarkers and will therefore potentially overestimate the performancecharacteristics in future tissue samples. To improve the generalisabiltyof the estimates a modified jackknife resampling technique was used tocalculate a less biased value for each characteristic.

Results

A range of univariate statistical tests were applied on Affymetrixoligonucleotide microarray data to reveal human genes that could be usedto discriminate colorectal neoplastic tissues from non-neoplastictissues. There were further identified a number of gene transcripts thatappear to be useful for differentiating colorectal adenomas fromcolorectal carcinoma. Also identified were a subset of these transcriptsthat may have particular diagnostic utility due to the protein productsbeing either secreted or displayed on the cell surface of epithelialcells. Finally, there were identified a further subset of transcriptsexpressed specifically in neoplastic tissues and at low- ornear-background levels in non-neoplastic tissues.

Genes Differentially Expressed in Neoplastic Tissues

From a total GeneChip set of 44,928 probesets it was determined thatover 11,000 probesets were differentially expressed by moderated t-testusing the limma package in BioConductor (G. K. Smyth, 2004 supra)employing conservative (Bonferroni) multiple test correction. When thislist was further filtered to include only those probesets demonstratinga 2-fold or greater mean expression change between the neoplastic andnon-neoplastic tissues, 560 probesets were found to be expressed lowerin neoplasias relative to normal tissues.

These 560 probesets were annotated using the most recent metadata andannotation packages available for the chips. The 560 underexpressedprobesets were mapped to 434 gene symbols.

Δ-expression ProbeSet ID Gene Symbol Maps DOWN 560 434

Hypothetical Markers Specific for Colorectal Neoplasia

While differential gene expression patterns are useful for diagnosticpurposes this project also seeks to identify diagnostic proteins shedinto the lumen of the gut by neoplastic colorectal epithelia. Todiscover candidate proteins, the list of differentially expressedtranscripts was filtered with a selection criteria aimed at identifyingmarkers specifically turned off in colorectal neoplasia tissues. Toidentify ‘off’ genes the filter criteria were designed to find geneswith i) neoplastic expression levels below a theoretical on/offthreshold and ii) normal signals at least 2-fold higher. The expressionprofile of an example transcript that is ‘turned-off’ in neoplastictissues is shown in FIG. 1.

Example 2 Probesets Elevated in Non-Neoplasia Relative to NeoplasticTissues

Differential expression analysis was applied to identify down-regulatedprobesets in Affymetrix gene chip data measuring RNA concentration in454 colorectal tissues including 161 adenocarcinoma specimens, 29adenoma specimens, 42 colitis specimens and 222 non-diseased tissues.Using conservative corrections for multiple hypothesis testing and a2-fold absolute fold change cut-off it was determined that 560 probesetsexhibit a decreased expression level in neoplastic tissues relative tonon-neoplastic controls. 560 of these probesets have been mapped to 434putative gene symbols based on transcript nucleotide sequence.

Validation/Hypothesis Testing

RNA expression levels of these candidates were measured in independentlyderived clinical specimens. 526 probesets were hybridised to RNAextracts from 68 clinical specimens comprising 19 adenomas, 19adenocarcinomas, and 30 non-diseased controls using a custom-designed‘Adenoma Gene Chip’. Thirty-four (34) probesets were not tested as theywere not included on the custom design. It was confirmed that 459 of 526of the target probesets (or directly related probesets with the samegene locus target) were likewise differentially expressed (P<0.05) inthese independently-derived tissues. The results of differentialexpression analysis of these 459 probesets is shown in Table 1.

The 372 of the 434 unique gene loci to which the 560 probesets areunderstood to hybridise were further tested. The remaining 62 genesymbols were not represented in the validation data. It was observedthat 328 of 372 gene symbols were represented in the validation data byat least one differentially expressed probeset and many symbols includedmultiple probesets against regions across the putative locus. A completelist of probesets that bind to target loci is shown in Table 2.

Conclusion

The candidate probesets and symbols shown in Tables 1 and 2.respectively, are differentially expressed lower in neoplasticcolorectal tissues compared to non-neoplastic controls.

Example 3 Probesets Demonstrating a Non-Neoplasia Specific Profile

During analysis of the discovery data, a novel expression profile wasobserved between neoplastic and non-neoplastic phenotypes. It washypothesized that a subset of quantitatively differentially expressedprobesets are furthermore qualitatively differentially expressed. Suchprobesets show no evidence of a gene expression activity in neoplastictissues, i.e. these probesets appear to be expressed above backgroundlevels in non-neoplastic tissues only. This observation and theresulting hypothesis are based on two principles:

-   1. That the majority of human transcripts that are present on a    genome-wide GeneChip (e.g. U133) will not likely be expressed in the    colorectal mucosa; and-   2. That microarray binding intensity for such ‘off’ probesets (to    labeled cRNA) will reflect technical assay background, i.e.    non-specific oligonucleotide binding.

To generate a list of non-neoplasia specific probesets the neoplasticintensity of differentially expressed probesets were compared with ahypothetical background signal threshold from across all probesets onthe chip. We note that, by design, all probesets in the candidate poolfrom which the ‘on’ transcripts are chosen are at least two foldover-expressed in the non-diseased tissues relative to diseased tissues.Combined, these criteria yield the subset of differentially expressedtranscript species that are specifically expressed in non-neoplastictissues.

This analysis demonstrated that 42 probesets corresponding toapproximately 41 gene loci exhibit a non-neoplasia specifictranscription expression profile.

Validation/Hypothesis Testing

The custom gene chip design precludes testing the non-neoplasia-specificprobesets using the same principles as used for discovery. Inparticular, the custom gene chip (by design) does not contain a largepool of probesets anticipated to hybridise to hypothetically‘off’/‘non-transcribed’ gene, transcripts. This is because the customgene chip design is heavily biased toward differentially expressedtranscripts in colorectal neoplastic tissues.

The usual differential expression testing (limma) was therefore appliedto these candidate probesets for specifically expressed innon-neoplastic tissues. Of the 37 (of 42) probesets on the custom genechip, 33 probesets (or probesets which bind to the same locus) weredifferentially expressed between the 38 neoplastic tissues (adenoma &cancer) and non-neoplastic controls. The results of these validationexperiments is shown in Table 3.

It was further aimed to test all probesets which are known to hybridiseto the gene loci to which the probesets claimed herein. Of the 41putative gene loci targeted by the probesets, 33 were present in thevalidation data. All thirty-three (33) of these 33 (100%) gene symbolsdemonstrated at least one hybridising probeset which was differentiallyexpressed in the neoplastic tissues. Results for these experiments,including all probesets that bind to each target locus in adifferentially expressed manner are shown in Table 4.

Example 4 Materials and Methods for Examples 2 and 3

Gene expression profiling data measured in 454 colorectal tissuespecimens including neoplastic, normal and non-neoplastic diseasecontrols was purchased from GeneLogic Inc (Gaithersburg, Md. USA). Foreach tissue specimen Affymetrix (Santa Clara, Calif. USA)oligonucleotide microarray data totaling 44,928 probesets (HGU133A &HGU133B, combined), experimental and clinical descriptors, and digitallyarchived microscopy images of histological preparations was received.Prior to applying discovery methods to these data, extensive qualitycontrol methods, including statistical exploration, review of clinicalrecords for consistency and histopathology audit of a random sample ofarrays was carried out. Microarrays that did not meet acceptable qualitycriteria were removed from the analysis.

Hypothesis Testing

Candidate transcription biomarkers were tested using a customoligonucleotide microarray of 25-mer oligonucleotide probesets designedto hybridise to candidate RNA transcripts identified during discovery.Differential expression hypotheses were tested using RNA extractsderived from independently collected clinical samples comprising 30normal colorectal tissues, 19 colorectal adenoma tissues, and 19colorectal adenocarcinoma tissues. Each RNA extract was confirmed tomeet strict quality control criteria.

Colorectal Tissue Specimens

All tissues used for hypothesis testing were obtained from a tertiaryreferral hospital tissue bank in metropolitan Adelaide, Australia(Repatriation General Hospital and Flinders Medical Centre). Access tothe tissue bank for this research was approved by the Research andEthics Committee of the Repatriation General Hospital and the EthicsCommittee of Flinders Medical Centre. Informed patient consent wasreceived for each tissue studied.

Following surgical resection, specimens were placed in a sterilereceptacle and collected from theatre. The time from operative resectionto collection from theatre was variable but not more than 30 minutes.Samples, approximately 125 mm3 (5×5×5 mm) in size, were taken from themacroscopically normal tissue as far from pathology as possible, definedboth by colonic region as well as by distance either proximal or distalto the pathology. Tissues were placed in cryovials, then immediatelyimmersed in liquid nitrogen and stored at −150° C. until processing.

RNA Extraction

RNA extractions were performed using Trizol® reagent (Invitrogen,Carlsbad, Calif., USA) as per manufacturer's instructions. Each samplewas homogenised in 3004 of Trizol reagent using a modified Dremel drilland sterilised disposable pestles. Additional 2041 of Trizol reagent wasadded to the homogenate and samples were incubated at RT for 10 minutes.100 μL of chloroform was then added, samples were shaken vortexed for 15seconds, and incubated at RT for 3 further minutes. The aqueous phasecontaining target RNA was obtained by centrifugation at 12,000 rpm for15 min, 40° C. RNA was then precipitated by incubating samples at RT for10 min with 250 μl of isopropanol. Purified RNA precipitate wascollected by centrifugation at 12,000 rpm for 10 minutes, 40° C. andsupernatants were discarded. Pellets were then washed with 1 mL 75%ethanol, followed by vortexing and centrifugation at 7,500 g for 8 min,40° C. Finally, pellets were air-dried for 5 min and resuspended in 80μL of RNase free water. To improve subsequent solubility samples wereincubated at 55° C. for 10 min. RNA was quantified by measuring theoptical density at A260/280 nm. RNA quality was assessed byelectrophoresis on a 1.2% agarose formaldehyde gel.

Gene Chip Processing

To test hypotheses related to biomarker candidates for colorectalneoplasia RNA extracts were assayed using a custom GeneChip designed byus in collaboration with Affymetrix (Santa Clara, Calif. USA). Thesecustom GeneChips were processed using the standard Affymetrix protocoldeveloped for the HU Gene ST 1.0 array described in (Affy:WTAssay).

Statistical Software and Data Processing

The R statistics environment R and BioConductor libraries (BioConductor,www.bioconductor.org) (BIOC) was used for most analyses. To map probesetIDs to gene symbol on the Custom GeneChip hgu133plus2 library version2.2.0 was used which was assembled using Entrez Gene data downloaded onApr. 18 12:30:55 2008 (BIOC).

Hypothesis Testing of Differentially Expressed Biomarkers

To assess differential expression between tissue classes the Student's ttest for equal means between two samples or the robust variant providedby the limma library (Smyth)(limma) was used. To mitigate the impact offalse discovery due to multiple hypothesis testing, a Bonferroniadjustment to P values in the discovery process (MHT:Bonf) was applied.For hypotheses testing the slightly less conservative multiplehypothesis testing correction of Benjamini & Hochberg, which aims tocontrol the false discovery rate of solutions (MHT:BH), was applied.

Discovery of Tissue-Specific Gene Expression Patterns

Discovery methods using gene expression data often yield numerouscandidates, many of which are not suitable for commercial productsbecause they involve subtle gene expression differences that would bedifficult to detect in laboratory practice. Pepe et al. note that the‘ideal’ biomarker is detectable in tumor tissue but not detectable (atall) in non-tumour tissue (Pepe:biomarker:development.) To bias thediscovery toward candidates that meet this criteria, an analysis methodwas developed that aims to enrich the candidates for biomarkers whosequalitative absence or presence measurement is diagnostic for thephenotype of interest. This method attempts to select candidates thatshow a prototypical ‘turned-on’ or ‘turned-off’ pattern relative to anestimate of the background/noise expression across the chip. It istheorized that such RNA transcripts are more likely to correlate withdownstream translated proteins with diagnostic potential or to predictupstream genomic changes (e.g. methylation status) that could be useddiagnostically. This focus on qualitative rather than quantitativeoutcomes may simplify the product development process for suchbiomarkers.

The method is based on the assumption that the pool of extracted RNAspecies in any given tissue (e.g. colorectal mucosae) will specificallybind to a relatively small subset of the full set of probesets on aGeneChip designed to measure the whole genome. On this assumption, it isestimated that most probesets on a full human gene chip will not exhibitspecific, high-intensity signals.

This observation is utilised to approximate the background or‘non-specific binding’ across the chip by choosing a theoretical levelequal to the value of e.g. lowest 25% quantile of the ranked meanvalues. This quantile can be arbitrarily set to some level below whichthere is made a reasonable assumption that the signals do not representabove-background RNA binding. Finally, this background estimate is usedas a threshold to estimate the ‘OFF’ probesets in an experiment for,say, the non-neoplastic tissue specimens.

Conversely, it is further hypothesized that probesets which are 1)expressed above this theoretical threshold level and 2) atdifferentially higher levels in the tumour specimens may be a tumourspecific candidate biomarker. It is noted that in this case the conceptof ‘fold-change’ thresholds can also be conveniently applied to furtheremphasize the concept of absolute expression increases in a putatively‘ON’ probeset.

Given the assumption of low background binding for a sizeable fractionof the measured probesets, this method was only used in the largeGeneLogic data and discovery. To construct a filter for hypothetically‘turned on’ biomarker in the GeneLogic discovery data, the meanexpression level for all 44,928 probesets across the full range of 454tissues was estimated. The 44,928 mean values were then ranked and theexpression value equivalent to the 25th percentile across the datasetcalculated. This arbitrary threshold was chosen because the majority oftranscripts (and presumably more than 25%) in a given specimen shouldexhibit low concentration which effectively transcriptional silence.Thus this threshold represents a conservative upper bound for what isestimated is non-specific, or background, expression.

Example 5 DNA Methylation Data

Assays were developed for detection of methylation in the promoterregions the eight down-regulated genes in Table 5. Methods forbisulphite treatment of DNA and assays for determination of DNAmethylation levels, including MSP and COBRA, are described in Clark etal. (2006).

Five MSP assays used the primer pairs shown in TABLE 7. A control PCRfor unbiased amplification of the CAGE gene was used to determine thequantity of input DNA to provide a reference for quantification of thelevel of methylation of each gene. For PCRs, 25 μL reactions in BioradiQ SyBr Green Super Mix contained 5 ng of bisulphite-treated DNAs (1 ngfor cell line assays and 6 ng for clinical specimens) and 200 nM offorward and reverse primers. PCR cycling conditions were:

-   -   95.0° C. for 2 min    -   Followed by 50 cycles of    -   95.0° C./15 sec    -   Temp° C./30 sec    -   72.0° C./30 sec

Where “Temp” is the re-annealing temperature optimised for each gene asshown in Table yy.

For the DF gene, 3 preliminary cycles were done using a 95.0° C. meltingtemperature, followed by 50 cycles with a lower, 84.0° C. meltingtemperature (to reduce nonspecific amplification).

A standard curve was generated using DNA methylated with M.SssImethylase (100% methylated) and DNA that had been in vitro amplifiedusing Phi29 DNA polymerase (0% methylation).

COBRA assays were developed for three genes as shown in TABLE 8. PCRswere setup as above with cycling conditions:

-   -   95.0° C. for 2 min    -   Followed by 50 cycles of    -   95.0° C./15 sec    -   Temp° C./30 sec    -   72.0° C./30 sec

After PCR, 10 μL of PCR product was digested with the appropriate enzyme(TABLE 8), digestion products analysed by gel electrophoresis andmethylation levels determined semiquantitatively.

The methylation state of the eight genes was determined in fourcolorectal cancer cell lines, Caco2, HCT116, HT29 and SW480 as well asnormal blood DNA and the normal lung fibroblast cell line, MRC5. Thelevel of methylation in summarised in Table 5. The promoter regions ofall eight genes show strong methylation in 2 or 3 of the four colorectalcancer cell lines tested. All showed a lack or low level of methylationin DNA from normal blood DNA and the fibroblast cell line MRC5, exceptfor methylation of DF in MRC5.

For two of these genes, MAMDC2 and GPM6B analysis has been extended to aset of 12 adenoma, 18 cancer and 22 matched normal tissue samples (FIG.2, A and B).

For MAMDC2 quantitative analysis demonstrated that 2 of 12 adenomas and6 of 18 cancer samples showed elevated methylation compared with thehighest level observed in normal tissue samples. Methylation levels ofthe GPM6B gene were determined by semiquantitative COBRA assays, scoredon a scale of 0 to 5 based on visual inspection of restrictiondigestions. A clear trend toward increasing promoter methylation inprogression from normal to adenoma to cancer was evident (FIG. 2, panelB).

These data demonstrate for a number of examples of the down-regulatedgenes that such downregulation in colorectal cancer cell lines andprimary neoplasia tissue may be associated with DNA methylation and thatassays of DNA methylation can be used to discriminate cancer and normaltissue.

Example 6 Determine Gene Identity of a Nucleic Acid Sequence of Interestwhich is Define by an Affymetrix Probeset

BLAST the Sequence of Interest Using Online Available Basic LocalAlignment Search Tools [BLAST]. e.g. NCBI/BLAST

-   -   (http://blast.ncbi.nlm.nih.gov/Blast.cgi)

-   (a) Select “Human” in BLAST ASSEMBLED GENOMES on the web page    http://blast.ncbi.nlm.nih.gov/Blast.cgi

-   (b) Leave the default settings, i.e.:    -   Database: Genome (all assemblies)    -   Program: megaBLAST: compare highly related nucleotide sequences    -   Optional parameters: Expect: 0.01, Filter: default,        Descriptions: 100, Alignments: 100

-   (c) Copy/Paste Sequence into the “BLAST” window

-   (d) Click “Begin Search”

-   (e) Click “View Report”

Assessment of the Open BLAST Search Results

Multiple significant sequence alignments may be identified when“blasting” the sequence.

Identify Gene Nomenclature of the Identified Sequence Match

-   (a) Click the link to one of the identified hits-   (b) The new page will schematically depict the position of the hit    on one chromosome. It will be apparent which gene is hit.-   (c) Retrieve the “hit” sequence clicking on the link-   (d) Do a search for the gene in the provided “search” window. This    provides the gene nucleotide coordinates for the gene.

Determine Promiscuity of Sequence

-   (a) Open the NCBI/BLAST tool,    (http://blast.ncbi.nlm.nih.gov/Blast.cgi)-   (b) Click on “nucleotide Blast” under “basic BLAST”-   (c) Copy/paste the sequence of interest into the “Query Sequence”    window-   (d) Click “Blast”.    Assessment of the nBLAST Search Results of the Sequence-   (a) The nBLAST exercise with the Sequence may result in multiple    Blast hits of which some accession entry numbers are listed in    “Description”.-   (b) These hits should be reviewed.

Determine Location of the Sequence in the Gene

The Ensembl database is an online database, which produces and maintainsautomatic annotation selected eukaryotic genomes(www.ensembl.org/index.html)

Identify Location of the Sequence in the Gene

-   (a) Set “Search” to Homo Sapiens, Type “the gene name” in the    provided Search Field Ensemble.org/index.html)-   (b) Click “Go”-   (c) Click the “vega protein_coding Gene: OTTHUMG000000144184” link    to get an annotation report-   (d) Click on “Gene DAS Report” to retrieve information regarding    Alternative splice site database: Type “the gene name” in search    field    -   Click on “the gene entry”    -   Scroll down to “evidences”    -   Review alternative splice sites    -   Click “Confirmed intron/exons” to get a list of coordinates for        the exons & introns.        Alternative Splicing and/or Transcription

The AceView Database provides curated and non-redundant sequencerepresentation of all public mRNA sequences. The database is availablethrough NCBI: http://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/

Further Investigation of the Gene mRNA Transcripts

-   (a) Type “the gene name” into the provided “search” field-   (b) Click “Go”-   (c) The following information is available from the resulting entry    in AceView:    -   The number of cDNA clones from which the gene is constructed (ie        originated-from experimental work involving isolation of mRNA)    -   The mRNAs predicted to be produced by the gene    -   The existence of non-overlapping alternative exons and validated        alternative polyadenylation sites    -   The existence of truncations    -   The possibility of regulated alternate expression    -   Introns recorded as participating in alternatively splicing of        the gene-   (d) Classic splice site motives    Application of Method to LOC643911/hCG_(—)1815491

Materials and Methods Extraction of RNA

RNA extractions were performed using Trizol® reagent (Invitrogen,Carlsbad, Calif., USA) as per manufacturer's instructions. Each samplewas homogenised in 300 μL of Trizol reagent using a modified dremeldrill and sterilised disposable pestles. Additional 200 μL of Trizolreagent was added to the homogenate and samples were incubated at RT for10 minutes. 100 μL of chloroform was then added, samples were shakenvortexed for 15 seconds, and incubated at RT for 3 further minutes. Theaqueous phase containing target RNA was obtained by centrifugation at12,000 rpm for 15 min, 40° C. RNA was then precipitated by incubatingsamples at RT for 10 min with 250 μL of isopropanol. Purified RNAprecipitate was collected by centrifugation at 12,000 rpm for 10minutes, 40° C. and supernatants were discarded. Pellets were thenwashed with 1 mL 75% ethanol, followed by vortexing and centrifugationat 7,500 g for 8 min, 40° C. Finally, pellets were air-dried for 5 minand resuspended in 804 of RNase free water. To improve subsequentsolubility samples were incubated at 55. C for 10 min. RNA wasquantified by measuring the optical density at A260/280 nm. RNA qualitywas assessed by electrophoresis on a 1.2% agarose formaldehyde gel.

Gene Chip Processing

RNA samples to analyze on Human Exon 1.0 ST GeneChips were processedusing the Affymetrix WT target labeling and control kit (part#900652)following the protocol described in (Affymetrix 2007 P/N 701880 Rev.4).Briefly: First cycle cDNA was synthesized from 100 ng ribosomal reducedRNA using random hexamer primers tagged with T7 promoter sequence. andSuperScript II (Invitrogen, Carlsbad Calif.), this was followed by DNAPolymerase I synthesis of the second strand cDNA. Anti-sense cRNA wasthen synthesized using T7 polymerase. Second cycle sense cDNA was thensynthesised using SuperScript H, dNTP+dUTP, and random hexamers toproduce sense strand cDNA incorporating uracil. This single strandeduracil containing cDNA was then fragmented using a combination of uracilDNA glycosylase (UDG) and apurinic/apyrimidinic endonuclease1 (APE 1).Finally the DNA was biotin labelled using terminal deoxynucleotidyltransferase (TdT) and the Affymetrix proprietary DNA Labeling reagent.Hybridization to the arrays was carried out at 45° C. for 16-18 hours.

Washing and staining of the hybridized GeneChips was carried out usingthe Affymetrix Fluidics Station 450 and scanned with the AffymetrixScanner 3000 following recommended protocols.

SYBR Green Based Quantitative Real Time-PCR

Quantitative real time polymerase chain reaction was performed on RNAisolated from clinical samples for the amplification and detection ofthe various hCG_(—)1815491 transcripts.

Firstly cDNA was synthesized from 2 ug of total RNA using the AppliedBiosystems High Capacity Reverse transcription Kit (P/N 4368814). Aftersynthesis the reaction was diluted 1:2 with water to obtain a finalvolume of 40 ul and 1 ul of this diluted cDNA used in subsequent PCRreactions.

PCR was performed in a 25 ul volume using 12.5 ul Promega 2×PCR mastermix (P/N M7502), 1.5 ul 5 uM forward primer, 1.5 ul 5 uM reverse primer,7.875 ul water, 0.625 ul of a 1:3000 dilution of 10,000× stock of SYBRgreen 1 pure dye (Invitrogen P/N S7567), and 1 ul of cDNA.

Cycling conditions for amplification were 95° for 2 minutes×1 cycle, 95°for 15 seconds and 60° for 1 minute×40 cycles. The amplificationreactions were performed in a Corbett Research Rotor-Gene RG3000 or aRoche LightCycler480 real-time PCR machine. When the RocheLightCycler480 real-time PCR machine was used for amplification thereaction volume was reduced to 10 ul and performed in a 384 well platebut the relative ratios between all the components remained the same.Final results were calculated using the ΔΔCt method with the expressionlevels of the various hCG_(—)1815491 transcripts being calculatedrelative to the expression level of the endogenous house keeping geneHPRT.

End-Point PCR

End point PCR was performed on RNA isolated from clinical samples forthe various hCG_(—)1815491 transcripts. Conditions were identical tothose described for the SYBR green assay above but with the SYBR greendye being replaced with water. The amplification reactions wereperformed in a MJ Research PTC-200 thermal cycler. 2.5 μl of theamplified products were analysed on 2% agarose E-gel (Invitrogen) alongwith a 100-base pair DNA Ladder Marker.

Results

The nucleotide structure and expression levels of transcripts related tohCG_(—)1815491 was analysed based on the identification of diagnosticutility of Affymetrix probesets 238021_s_at and 238022_at from the genechip analysis.

The gene hCG_(—)1815491 is currently represented in NCBI as a singleRefSeq sequence; XM_(—)93911. The RefSeq sequence of hCG_(—)1815491 isbased on 89 GenBank accessions from 83 cDNA clones. Prior to March 2006,these clones were predicted to represent two overlapping genes,LOC388279 and LOC650242 (the latter also known as LOC643911). In March2006, the human genome database was filtered against clonerearrangements, co-aligned with the genome and clustered in a minimalnon-redundant way. As a result, LOC388272 and LOC650242 were merged intoone gene named hCG_(—)1815491 (earlier references to hCG_(—)1815491 are:LOC388279, LOC643911, LOC650242, XM_(—)944116, AF275804, XM_(—)373688).

It has been determined that the Ref Sequence, which is defined by thegenomic coordinates 8579310 to 8562303 on human chromosome 16 as definedby the NCBI contig reference NT_(—)010498.15|Hs16_(—)10655, NCBI 36March 2006 genome encompasses hCG_(—)1815491. The 10 predicted RNAvariants derived from this gene have been aligned with the genomicnucleotide sequence residing in the map region 8579310 to 8562303. Thisalignment analysis revealed the existence of at least 6 exons of whichseveral are alternatively spliced. The identified exons are in contrastto the just 4 exons specified in the NCBI hCG_(—)1815491 RefSeqXM_(—)93911. Two additional putative exons were also identified in theRef Sequence by examination of included probesets on Affymetrix GenechipHuGene Exon 1.0 that target nucleotide sequences embedded in the RefSequence. The identified and expanded exon-intron structure ofhCG_(—)1815491 have been used to design specific oligonucleotideprimers, which allowed measurement of the expression of RNA variantsgenerated from the Ref Sequence by using PCR-based methodology (FIG. 4)

Tables

The probeset designations include both HG-133plus2 probeset IDs andHuman Gene 1.0ST array probe ids. The latter can be conveniently mappedto Transcript Cluster ID using the Human Gene 1.0ST probe tab fileprovided by Affymetrix(http://www.affymetrix.com/Auth/analysis/downloads/na22/wtgene/HuGene-1_(—)0-st-v1.probe.tab.zip).Using publicly available software such as NetAffx (provided byAffymetrix), the Transcript Cluster ID may be further mapped to genesymbol, chromosomal location, etc.

Table 1

Probesets demonstrated to be expressed higher in non-neoplastic tissuesrelative to neoplastic controls. TargetPS: Affymetrix HG-U133plus2probeset id; Symbol: putative gene symbol corresponding to targetprobeset id—multiple symbol names indicate the possibility of probesethybridisation to multiple gene targets; Signif. FDR: Adjusted p-valuefor mean difference testing between RNA extracted from neoplasia andnon-neoplastic tissues. Adjustment is made using Benjamini & Hochbergcorrection for multiple hypothesis testing (Benjamini and Hochberg,1995); D.value50: Diagnostic effectiveness parameter estimatecorresponding to the area of a receiver operator characteristic ROC.This parameter provides a convenient estimate of diagnostic utility andis described in (Saunders, 2006); FC: fold change between meanexpression level of non-neoplasia vs. neoplasia; Sens-Spec: Estimate ofdiagnostic performance corresponding to the ROC curve pointdemonstrating equal sensitivity and specificity; CI (95): 95% confidenceinterval of sensitivity and specificity estimates.

Table 2

Evidence of multiple probesets which correspond to gene symbols claimedherein exhibiting RNA concentration differences between non-neoplastictissues and neoplastic controls. Symbol: gene symbol; ValidPS_DOWN:Affymetrix probeset IDs demonstrating statistically significantoverexpression in non-neoplastic RNA extracts relative to neoplasticcontrols. Signif. FDR: Adjusted p-value for mean difference testingbetween RNA extracted from neoplasia and non-neoplastic tissues.Adjustment is made using Benjamini & Hochberg correction for multiplehypothesis testing (Benjamini and Hochberg, 1995); D.value50: Diagnosticeffectiveness parameter estimate corresponding to the area of a receiveroperator characteristic ROC. This parameter provides a convenientestimate of diagnostic utility and is described in (Saunders, 2006); FC:fold change between mean expression level of non-neoplasia vs.neoplasia; Sens-Spec: Estimate of diagnostic performance correspondingto the ROC curve point demonstrating equal sensitivity and specificity;CI (95): 95% confidence interval of sensitivity and specificityestimates.

Table 3

Probesets which demonstrate a qualitatively (in addition toquantitative) elevated profile in non-neoplastic tissues relative toneoplastic controls. TargetPS: Affymetrix HG-U133plus2 probeset id;Symbol: putative gene symbol corresponding to target probesetid—multiple symbol names indicate the possibility of probesethybridisation to multiple gene targets; Signif. FDR: Adjusted p-valuefor mean difference testing between RNA extracted from neoplasia andnon-neoplastic tissues. Adjustment is made using Benjamini & Hochbergcorrection for multiple hypothesis testing (Benjamini and Hochberg,1995); D.value50: Diagnostic effectiveness parameter estimatecorresponding to the area of a receiver operator characteristic ROC.This parameter provides a convenient estimate of diagnostic utility andis described in (Saunders, 2006); FC: fold change between meanexpression level of non-neoplasia vs. neoplasia; Sens-Spec: Estimate ofdiagnostic performance corresponding to the ROC curve pointdemonstrating equal sensitivity and specificity; CI (95): 95% confidenceinterval of sensitivity and specificity estimates.

Table 4

Evidence of multiple probesets which correspond to gene symbols claimedherein exhibiting qualitative changes in RNA concentration innon-neoplastic tissues compared to neoplastic tissues. Symbol: genesymbol; ValidPS_DOWN: Affymetrix probeset IDs demonstratingstatistically significant overexpression in neoplastic RNA extractsrelative to non-neoplastic controls. Signif. FDR: Adjusted p-value formean difference testing between RNA extracted from neoplasia andnon-neoplastic tissues. Adjustment is made using Benjamini & Hochbergcorrection for multiple hypothesis testing (Benjamini and Hochberg,1995); D.value50: Diagnostic effectiveness parameter estimatecorresponding to the area of a receiver operator characteristic ROC.This parameter provides a convenient estimate of diagnostic utility andis described in (Saunders, 2006); FC: fold change between meanexpression level of non-neoplasia vs. neoplasia; Sens-Spec: Estimate ofdiagnostic performance corresponding to the ROC curve pointdemonstrating equal sensitivity and specificity; CI (95): 95% confidenceinterval of sensitivity and specificity estimates.

Those skilled in the art will appreciate that the invention describedherein is susceptible to variations and modifications other than thosespecifically described. It is to be understood that the inventionincludes all such variations and modifications. The invention alsoincludes all of the steps, features, compositions and compounds referredto or indicated in this specification, individually or collectively, andany and all combinations of any two or more of said steps or features.

TABLE 1 Sens- TargetPS Symbol Signif. FDR D.val5 FC Spec CI (95)230788_at SPTLC3:GCNT2 2.16E−27 3.9512 13.36 97.6 94.2-99.2 207502_atGUCA2B 7.04E−25 3.6279 51.78 96.5 92.3-98.6 207003_at GUCA1B 7.32E−253.565 10.7 96.3   92-98.5 206208_at CA4 1.73E−24 3.6263 10.41 96.592.4-98.6 206209_s_at CA4 1.73E−24 3.6265 10.41 96.5 92.3-98.6 203908_atLOC727995:SLC4A4:LOC730895 2.23E−23 3.6298 3.58 96.5 92.4-98.6 206784_atAQP8 2.98E−22 3.3284 10.82 95.2 90.3-97.9 205950_s_at CA1 3.15E−22 3.36838.27 95.4 90.6-98   209735_at ABCG2 1.09E−21 3.2584 31.53 94.889.7-97.7 230830_at OSTbeta 6.23E−21 3.1861 7.15 94.4 89.2-97.5223754_at MGC13057 6.94E−21 3.2036 3.18 94.5 89.3-97.5 228195_atMGC13057 6.94E−21 3.2023 3.18 94.5 89.4-97.5 228706_s_at CLDN23 4.27E−203.0757 3.47 93.8 88.2-97.1 228707_at CLDN23 4.27E−20 3.072 3.47 93.888.3-97.1 223551_at PKIB 5.94E−20 3.1219 3.28 94.1 88.6-97.3 231120_x_atPKIB 5.94E−20 3.1226 3.28 94.1 88.6-97.3 226492_at SEMA6D 6.07E−203.0898 4.27 93.9 88.4-97.2 220026_at CLCA4 1.25E−19 3.1909 16.3 94.589.2-97.5 224836_at TP53INP2 1.45E−19 3.0248 3.78 93.5 87.9-96.9220834_at MS4A12 2.13E−19 3.29 7.15 95   90-97.8 224412_s_at TRPM62.25E−19 3.01 7.5 93.4 87.7-96.8 220037_s_at XLKD1 3.60E−19 2.9412 7.4492.9 87.1-96.6 219059_s_at XLKD1 3.60E−19 2.942 7.44 92.9   87-96.6209612_s_at ADH1B:ADH1A 4.70E−19 3.0183 4.67 93.4 87.7-96.9 209613_s_atADH1B:ADH1A 4.70E−19 3.0147 4.67 93.4 87.7-96.9 200845_s_atLOC389249:PRDX6 5.56E−19 2.8412 2.76 92.2 86.1-96.1 209301_at CA25.87E−19 2.9662 9.22 93.1 87.3-96.7 208399_s_at EDN3 6.42E−19 2.934211.21 92.9   87-96.5 228961_at MIER3 9.14E−19 2.9183 3.91 92.8 86.9-96.5231975_s_at MIER3 9.14E−19 2.9172 3.91 92.8 86.8-96.4 204719_at ABCA81.26E−18 2.9172 6.82 92.8 86.8-96.5 207761_s_at METTL7A 1.35E−18 3.12471.93 94.1 88.6-97.3 207977_s_at DPT 1.53E−18 2.8967 9.07 92.6 86.6-96.4213068_at DPT 1.53E−18 2.8973 9.07 92.6 86.7-96.4 213071_at DPT 1.53E−182.8962 9.07 92.6 86.7-96.4 218756_s_at MRM1:MGC4172 1.74E−18 2.9041 3.7492.7 86.6-96.4 212288_at FNBP1:C1orf85:CCT3 1.76E−18 3.0475 2.04 93.688-97 204036_at EDG2 2.44E−18 2.8853 3.19 92.5 86.4-96.3 202037_s_atSFRP1 2.77E−18 2.8647 15.53 92.4 86.3-96.2 206143_at SLC26A3 4.18E−182.9202 21.4 92.8 86.9-96.5 215657_at SLC26A3 4.18E−18 2.9226 21.4 92.886.9-96.5 231773_at ANGPTL1 1.42E−17 2.7938 4.64 91.9 85.6-95.9205480_s_at UGP2 1.64E−17 2.7911 2.41 91.9 85.6-95.9 204955_at SRPX1.79E−17 2.7753 3.91 91.7 85.5-95.8 222722_at OGN 2.25E−17 2.7048 13.6791.2 84.8-95.4 202555_s_at MYLK 2.33E−17 2.773 3.99 91.7 85.4-95.8224823_at MYLK 2.33E−17 2.7727 3.99 91.7 85.4-95.8 225575_at LIFR2.45E−17 2.7823 6.36 91.8 85.5-95.8 214142_at LOC653808:ZG16 2.51E−172.8119 8.14 92 85.8-95.9 206710_s_at EPB41L3 2.62E−17 2.8298 2.51 92.185.9-96.1 205464_at SCNN1B 3.20E−17 2.7209 16.15 91.3 84.9-95.5220812_s_at HHLA2 3.47E−17 2.6717 10.02 90.9 84.4-95.3 203913_s_at HPGD3.65E−17 2.8441 3.21 92.2 86.1-96.1 203914_x_at HPGD 3.65E−17 2.84563.21 92.3 86.1-96.1 211548_s_at HPGD 3.65E−17 2.8446 3.21 92.3 86.1-96.1211549_s_at HPGD 3.65E−17 2.8466 3.21 92.3 86.1-96.1 206198_s_at CEACAM73.96E−17 2.7882 10.4 91.8 85.5-95.9 206199_at CEACAM7 3.96E−17 2.785510.4 91.8 85.6-95.8 211848_s_at CEACAM7 3.96E−17 2.7882 10.4 91.885.6-95.8 226430_at SMAD5:RELL1 4.10E−17 2.6968 2.5 91.1 84.6-95.4202992_at C7 4.40E−17 2.7163 6.67 91.3 84.9-95.5 205112_at PLCE16.91E−17 2.7542 2.43 91.6 85.2-95.7 229839_at SCARA5 1.25E−16 2.68972.86 91.1 84.6-95.3 235849_at SCARA5 1.25E−16 2.6918 2.86 91.1 84.5-95.3209763_at CHRDL1 1.49E−16 2.6093 13.88 90.4 83.7-94.9 205259_at NR3C22.08E−16 2.5812 3.19 90.2 83.4-94.7 202242_at TSPAN7 2.13E−16 2.65193.68 90.8 84.1-95.1 203000_at STMN2 2.25E−16 2.6115 6.13 90.4 83.7-94.9203001_s_at STMN2 2.25E−16 2.6141 6.13 90.4 83.7-94.9 209074_s_atFAM107A 2.52E−16 2.6171 2.92 90.5 83.8-94.9 202920_at ANK2 2.59E−162.6499 6.76 90.7 84.1-95.1 213317_at CLIC5 3.68E−16 2.696 2.37 91.184.6-95.4 204697_s_at CHGA 5.54E−16 2.6087 7.21 90.4 83.7-94.9 212814_atKIAA0828 5.58E−16 2.5495 4.09 89.9   83-94.5 225275_at EDIL3 6.21E−162.6252 2.96 90.5 83.9-95   208370_s_at DSCR1 6.21E−16 2.6146 2.14 90.483.7-94.9 209147_s_at PPAP2A 6.43E−16 2.5961 2.4 90.3 83.6-94.8210946_at PPAP2A 6.43E−16 2.5967 2.4 90.3 83.5-94.8 202731_at PDCD48.67E−16 2.4558 2.6 89 82-94 219799_s_at DHRS9:GORASP2 1.09E−15 2.73681.51 91.4 85.1-95.6 223952_x_at DHRS9:GORASP2 1.09E−15 2.7334 1.51 91.4  85-95.6 224009_x_at DHRS9:GORASP2 1.09E−15 2.7359 1.51 91.4 85.1-95.6236313_at CDKN2B 1.34E−15 2.5442 10.09 89.8   83-94.5 231925_at P2RY11.41E−15 2.5354 3.6 89.8 82.9-94.4 238143_at LOC646627 1.58E−15 1.91425.02 83.1 74.8-89.4 224480_s_at LPAAT-THETA 2.06E−15 2.3867 2.63 88.481.1-93.5 212230_at PPAP2B 2.44E−15 2.5821 1.81 90.2 83.4-94.7207080_s_at PYY 3.50E−15 2.4811 11.71 89.3 82.3-94.1 205200_at CLEC3B4.65E−15 2.4426 4.46 88.9 81.8-93.8 228133_s_at NDE1 4.84E−15 2.514 1.9989.6 82.7-94.3 214038_at CCL8 5.75E−15 2.4504 7.51 89 81.9-93.9219014_at PLAC8 5.76E−15 2.4248 3.87 88.7 81.6-93.7 219796_s_at MUCDHL5.81E−15 2.4346 3.06 88.8 81.6-93.8 220075_s_at MUCDHL 5.81E−15 2.43543.06 88.8 81.7-93.8 215299_x_at SULT1A1:SULT1A2 7.17E−15 2.4231 3.3788.7 81.5-93.7 233565_s_at SDCBP2 9.28E−15 2.4871 2.37 89.3 82.3-94.1228885_at RPL24:LOC731365 1.23E−14 2.5555 1.63 89.9 83.1-94.6 209687_atCXCL12 1.54E−14 2.4322 3.79 88.8 81.7-93.8 218546_at C1orf115 1.95E−142.4106 2.95 88.6 81.4-93.6 205097_at SLC26A2 2.08E−14 2.4219 7.83 88.781.5-93.7 224959_at SLC26A2 2.08E−14 2.4229 7.83 88.7 81.6-93.7224963_at SLC26A2 2.08E−14 2.4205 7.83 88.7 81.5-93.7 204069_at MEIS12.49E−14 2.3759 5.44 88.3   81-93.4 223121_s_at SFRP2 3.05E−14 2.39377.39 88.4 81.2-93.5 223122_s_at SFRP2 3.05E−14 2.3967 7.39 88.581.2-93.5 209191_at TUBB3:MC1R:TUBB6 3.55E−14 2.3684 5.9 88.2 80.9-93.3201348_at GPX3 5.68E−14 2.36 2.57 88.1 80.8-93.2 214091_s_at GPX35.68E−14 2.3613 2.57 88.1 80.7-93.3 228766_at CD36 6.27E−14 2.4671 1.6589.1 82.1-94   221896_s_at HIGD1A 6.29E−14 2.3985 2.09 88.5 81.3-93.5201865_x_at NR3C1 7.65E−14 2.3539 2.51 88 80.6-93.2 211671_s_at NR3C17.65E−14 2.3517 2.51 88 80.7-93.2 206149_at LOC63928 8.09E−14 2.3513 3.288 80.7-93.2 228846_at MXD1 8.35E−14 2.4074 2.11 88.6 81.4-93.6225602_at C9orf19 1.74E−13 2.3619 1.95 88.1 80.9-93.3 225604_s_atC9orf19 1.74E−13 2.3646 1.95 88.1 80.8-93.3 201893_x_at DCN 2.05E−132.311 5.62 87.6 80.2-92.9 209335_at DCN 2.05E−13 2.3115 5.62 87.680.3-92.9 211813_x_at DCN 2.05E−13 2.3145 5.62 87.6 80.2-92.9211896_s_at DCN 2.05E−13 2.3124 5.62 87.6 80.2-92.9 204818_at HSD17B22.32E−13 2.196 4.76 86.4 78.7-92   204931_at TCF21 2.51E−13 2.306 2.3487.6 80.1-92.9 204438_at MRC1 2.72E−13 2.3105 2.6 87.6 80.2-92.9206262_at ADH1A:ADH1C 2.94E−13 2.3719 3.1 88.2 80.9-93.3 205433_at BCHE3.18E−13 2.2514 6.21 87 79.5-92.5 225242_s_at CCDC80 3.60E−13 2.23163.67 86.8 79.2-92.3 207980_s_at CITED2 5.29E−13 2.2709 1.64 87.279.7-92.6 209357_at CITED2 5.29E−13 2.2704 1.64 87.2 79.7-92.6208383_s_at PCK1 5.74E−13 2.3242 3.6 87.7 80.4-93   206385_s_atANK3:LOC729184:LOC731186 7.46E−13 2.2305 2.45 86.8 79.2-92.2 203305_atF13A1 8.82E−13 2.1821 4.74 86.2 78.6-91.8 206134_at ADAMDEC1 9.04E−132.2607 3.19 87.1 79.5-92.5 215118_s_at AHNAK:IGHG1 9.41E−13 2.3277 1.7387.8 80.3-93   217022_s_at AHNAK:IGHG1 9.41E−13 2.3254 1.73 87.880.4-93   223395_at ABI3BP 9.47E−13 2.2207 3.62 86.7   79-92.2 225626_atPAG1 1.11E−12 2.2136 2.68 86.6 78.9-92.1 213953_at KRT20 1.26E−12 2.09645.49 85.3 77.4-91.1 226594_at ENTPD5 1.43E−12 2.1687 3.01 86.1 78.4-91.8209373_at MALL 2.10E−12 2.1597 3.96 86 78.3-91.7 212713_at MFAP42.96E−12 2.1797 2.51 86.2 78.5-91.9 208920_at SRI 3.03E−12 2.0982 2.4385.3 77.4-91.1 201739_at SGK 3.12E−12 2.1221 4.08 85.6 77.8-91.3214696_at MGC14376 3.39E−12 2.1045 2.58 85.4 77.5-91.2 204034_at ETHE13.46E−12 2.2127 1.75 86.6   79-92.1 209667_at CES2 3.51E−12 2.102 2.8785.3 77.4-91.2 209668_x_at CES2 3.51E−12 2.0978 2.87 85.3 77.4-91.1213509_x_at CES2 3.51E−12 2.097 2.87 85.3 77.4-91.1 202291_s_atMGP:C12orf46 3.63E−12 2.1448 4.68 85.8   78-91.5 209167_at GPM6B4.04E−12 2.1568 3.59 86 78.2-91.6 209170_s_at GPM6B 4.04E−12 2.1581 3.5986 78.2-91.6 225720_at SYNPO2 5.07E−12 2.1053 6.43 85.4 77.5-91.2225721_at SYNPO2 5.07E−12 2.1069 6.43 85.4 77.5-91.2 225894_at SYNPO25.07E−12 2.1043 6.43 85.4 77.5-91.2 225895_at SYNPO2 5.07E−12 2.10696.43 85.4 77.5-91.2 227662_at SYNPO2 5.07E−12 2.1043 6.43 85.4 77.5-91.2206422_at GCG 5.58E−12 2.1185 12.56 85.5 77.7-91.3 205593_s_at PDE9A6.56E−12 2.1443 3.91 85.8   78-91.5 220376_at LRRC19 6.75E−12 2.076 4.5185 77.1-91   204130_at HSD11B2 6.97E−12 2.0896 2.53 85.2 77.3-91.1224964_s_at GNG2 7.25E−12 2.1405 1.91 85.8   78-91.5 219508_at GCNT38.39E−12 2.0843 3.94 85.1 77.2-91   211645_x_at No Symbol 9.19E−122.1536 1.61 85.9 78.2-91.6 212233_at No Symbol 9.19E−12 2.1541 1.61 85.978.1-91.6 212764_at No Symbol 9.19E−12 2.1541 1.61 85.9 78.1-91.6214777_at No Symbol 9.19E−12 2.1543 1.61 85.9 78.2-91.6 217235_x_at NoSymbol 9.19E−12 2.155 1.61 85.9 78.2-91.6 225710_at No Symbol 9.19E−122.1539 1.61 85.9 78.1-91.6 226333_at No Symbol 9.19E−12 2.1529 1.61 85.978.1-91.6 226834_at No Symbol 9.19E−12 2.154 1.61 85.9 78.1-91.6227061_at No Symbol 9.19E−12 2.152 1.61 85.9 78.1-91.6 228504_at NoSymbol 9.19E−12 2.1533 1.61 85.9 78.1-91.6 228507_at No Symbol 9.19E−122.1538 1.61 85.9 78.2-91.6 228640_at No Symbol 9.19E−12 2.1532 1.61 85.978.2-91.6 228854_at No Symbol 9.19E−12 2.1532 1.61 85.9 78.2-91.7236300_at No Symbol 9.19E−12 2.1532 1.61 85.9 78.2-91.6 242317_at NoSymbol 9.19E−12 2.1529 1.61 85.9 78.1-91.6 210524_x_at No Symbol9.19E−12 2.1554 1.61 85.9 78.2-91.7 224989_at No Symbol 9.19E−12 2.15261.61 85.9 78.2-91.6 227052_at No Symbol 9.19E−12 2.151 1.61 85.978.1-91.6 227682_at No Symbol 9.19E−12 2.1549 1.61 85.9 78.2-91.6235146_at No Symbol 9.19E−12 2.1527 1.61 85.9 78.2-91.7 207126_x_atUGT1A10:UGT1A7:UGT1A8: 9.98E−12 2.0677 4.56 84.9   77-90.9UGT1A1:UGT1A9:UGT1A6: UGT1A5:UGT1A3:UGT1A4 206094_x_atUGT1A10:UGT1A7:UGT1A8: 1.01E−11 2.0693 4.56 85   77-90.8UGT1A1:UGT1A9:UGT1A6: UGT1A5:UGT1A3:UGT1A4 208596_s_atUGT1A10:UGT1A7:UGT1A8: 1.01E−11 2.0662 4.56 84.9 76.9-90.8UGT1A1:UGT1A9:UGT1A6: UGT1A5:UGT1A3:UGT1A4 221305_s_atUGT1A10:UGT1A7:UGT1A8: 1.03E−11 2.0663 4.56 84.9   77-90.9UGT1A1:UGT1A9:UGT1A6: UGT1A5:UGT1A3:UGT1A4 204532_x_atUGT1A10:UGT1A7:UGT1A8: 1.18E−11 2.0678 4.56 84.9   77-90.9UGT1A1:UGT1A9:UGT1A6: UGT1A5:UGT1A3:UGT1A4 215125_s_atUGT1A10:UGT1A7:UGT1A8: 1.18E−11 2.0682 4.56 84.9   77-90.9UGT1A1:UGT1A9:UGT1A6: UGT1A5:UGT1A3:UGT1A4 209791_at PADI2 1.46E−112.0258 3.98 84.4 76.4-90.5 219669_at CD177 1.49E−11 2.0618 5.77 84.976.9-90.8 201539_s_at FHL1 1.63E−11 2.0448 3.25 84.7 76.7-90.7 201540_atFHL1 1.63E−11 2.0466 3.25 84.7 76.7-90.7 210298_x_at FHL1 1.63E−112.0438 3.25 84.7 76.7-90.6 210299_s_at FHL1 1.63E−11 2.0458 3.25 84.776.6-90.6 214505_s_at FHL1 1.63E−11 2.0459 3.25 84.7 76.7-90.6206576_s_at CEACAM1 2.66E−11 2.0448 2.85 84.7 76.7-90.7 209498_atCEACAM1 2.66E−11 2.0446 2.85 84.7 76.7-90.7 211889_x_at CEACAM1 2.66E−112.0471 2.85 84.7 76.7-90.7 202994_s_at FBLN1 2.82E−11 2.0183 3.55 84.476.3-90.4 202995_s_at FBLN1 2.82E−11 2.0191 3.55 84.4 76.3-90.4201427_s_at SEPP1 2.83E−11 2.034 4.15 84.5 76.5-90.6 212956_at TBC1D93.89E−11 2.1428 1.54 85.8   78-91.5 203963_at CA12 4.32E−11 2.0024 2.6584.2 76.1-90.2 204508_s_at CA12 4.32E−11 2.0029 2.65 84.2 76.2-90.3210735_s_at CA12 4.32E−11 2.0016 2.65 84.2 76.1-90.2 214164_x_at CA124.32E−11 2.0016 2.65 84.2 76.1-90.3 215867_x_at CA12 4.32E−11 2.00272.65 84.2 76.1-90.3 203881_s_at DMD 5.01E−11 2.0159 4.74 84.3 76.2-90.4213624_at SMPDL3A 5.84E−11 1.9409 3.14 83.4 75.2-89.6 226304_at HSPB66.16E−11 1.9486 6.88 83.5 75.4-89.8 206561_s_atLOC441282:AKR1B10:LOC340888 7.91E−11 1.9478 5.17 83.5 75.3-89.7203343_at UGDH 8.72E−11 1.9619 2.4 83.7 75.6-89.9 205892_s_at FABP19.02E−11 1.9694 6.54 83.8 75.6-89.9 206637_at P2RY14 1.31E−10 1.9821 283.9 75.8-90.1 202266_at TTRAP 1.59E−10 1.9147 2.2 83.1 74.9-89.4206000_at LOC642840:MEP1A:LOC389747: 2.07E−10 1.9873 3.17 84 75.9-90.1LOC644777 201496_x_at MYH11 2.15E−10 1.8577 5.35 82.4   74-88.8201497_x_at MYH11 2.15E−10 1.8599 5.35 82.4 74.1-88.8 207961_x_at MYH112.15E−10 1.859 5.35 82.4 74.1-88.9 201495_x_at MYH11 2.15E−10 1.85855.35 82.4   74-88.8 204388_s_at MAOA 2.49E−10 2.0297 2.18 84.5 76.4-90.5204389_at MAOA 2.49E−10 2.0256 2.18 84.4 76.5-90.5 212741_at MAOA2.49E−10 2.0267 2.18 84.5 76.5-90.5 214598_at CLDN8 2.92E−10 1.862 12.9682.4 74.2-88.9 202838_at FUCA1 4.24E−10 1.8831 2.03 82.7 74.4-89.1217897_at MB:FXYD6 6.39E−10 1.8109 2.92 81.7 73.3-88.3 220468_at ARL147.01E−10 1.8242 3.06 81.9 73.5-88.4 201920_at SLC20A1 7.65E−10 1.78494.04 81.4 72.9-88.1 210302_s_at MAB21L2 1.05E−09 1.7744 5.2 81.372.8-87.9 209114_at TSPAN1 1.16E−09 1.7896 2.16 81.5   73-88.1220266_s_at KLF4 1.19E−09 1.8515 2.27 82.3 73.8-88.7 221841_s_at KLF41.19E−09 1.8493 2.27 82.2 73.9-88.8 209283_at CRYAB 1.47E−09 1.7693 3.9181.2 72.7-87.8 223484_at C15orf48 1.54E−09 1.8189 3.07 81.8 73.4-88.4205412_at ACAT1 1.70E−09 1.8575 1.77 82.3 73.9-88.8 202888_s_at ANPEP2.04E−09 1.7673 8.18 81.2 72.6-87.8 225458_at EXOC3 2.25E−09 1.7957 3.1781.5 73.1-88.1 204834_at FGL2 2.64E−09 1.8245 2.07 81.9 73.4-88.5227265_at FGL2 2.64E−09 1.8246 2.07 81.9 73.6-88.4 228469_at PPID3.34E−09 1.8032 1.73 81.6 73.2-88.3 221004_s_at ITM2C 3.87E−09 1.70632.22 80.3 71.8-87.1 213921_at SST 4.16E−09 1.7652 6.14 81.1 72.6-87.8230087_at PRIMA1 4.74E−09 1.7085 2.75 80.4 71.8-87.2 201842_s_at EFEMP15.80E−09 1.8196 1.69 81.9 73.4-88.4 222162_s_at ADAMTS1 6.42E−09 1.74672.37 80.9 72.3-87.6 210517_s_at AKAP12 7.41E−09 1.7454 2.83 80.972.3-87.6 227529_s_at AKAP12 7.41E−09 1.7437 2.83 80.8 72.3-87.6228750_at COL14A1 7.60E−09 1.7813 1.67 81.3 72.9-88   219948_x_atLOC642329:UGT2A3 8.64E−09 1.7422 4.89 80.8 72.2-87.5 208131_s_at PTGIS9.15E−09 1.7212 3.98 80.5 71.9-87.3 207432_at BTN2A2:BEST2 9.19E−091.7179 3.63 80.5 71.9-87.3 219607_s_at MS4A4A:LOC643680 9.59E−09 1.81971.55 81.9 73.4-88.4 204688_at SGCE 1.02E−08 1.7438 2.03 80.8 72.3-87.6207134_x_at TPSB2 1.24E−08 1.3713 1.87 75.4 66.3-82.9 209156_s_at COL6A21.30E−08 1.68 2.08 80 71.3-86.8 202741_at PRKACB 1.30E−08 1.7217 2.1880.5 71.9-87.3 202742_s_at PRKACB 1.30E−08 1.721 2.18 80.5 71.9-87.3200795_at SPARCL1 1.33E−08 1.6379 2.85 79.4 70.7-86.3 219543_at PBLD1.38E−08 1.6981 2.74 80.2 71.6-87.1 225207_at PDK4 1.45E−08 1.705 3.0280.3 71.7-87.2 202222_s_at SPEG:LOC729871:DES 1.47E−08 1.7229 6.66 80.6  72-87.3 214027_x_at SPEG:LOC729871:DES 1.47E−08 1.7254 6.66 80.6  72-87.4 239272_at MMP28 1.80E−08 1.6622 2.47 79.7   71-86.6 222453_atTHEM4:CYBRD1 1.84E−08 1.6934 2.7 80.1 71.6-87   212195_at MAGEA4:IL6ST1.87E−08 1.764 1.58 81.1 72.6-87.8 203980_at FABP4 2.01E−08 1.6762 5.5579.9 71.3-86.8 211985_s_at CALM1 2.12E−08 1.6839 1.72 80 71.4-86.9221747_at TNS1:AKAP9 2.21E−08 1.7434 2.01 80.8 72.2-87.5 221748_s_atTNS1:AKAP9 2.21E−08 1.7409 2.01 80.8 72.3-87.5 201324_at EMP1 2.59E−081.7149 1.95 80.4 71.9-87.3 212397_at LOC643244:RDX 3.06E−08 1.7431 1.980.8 72.3-87.6 205382_s_at CFD 3.06E−08 1.6462 2.81 79.5 70.8-86.4201141_at GPNMB 3.11E−08 1.6928 1.99 80.1 71.5-87   205683_x_at TPSAB1,TPSAB1 3.52E−08 1.7075 1.93 80.3 71.8-87.1 210084_x_at TPSAB1, TPSAB13.52E−08 1.7045 1.93 80.3 71.8-87.1 215382_x_at TPSAB1, TPSAB1 3.52E−081.7091 1.93 80.4 71.7-87.2 216474_x_at TPSAB1, TPSAB1 3.52E−08 1.70691.93 80.3 71.7-87.2 227006_at PPP1R14A 3.54E−08 1.619 2.51 79.170.3-86.1 242601_at LOC253012 3.59E−08 1.6517 4.46 79.6 70.8-86.5212730_at DMN 4.36E−08 1.6046 4.05 78.9 70.2-86   226818_at MPEG14.58E−08 1.6466 1.86 79.5 70.8-86.5 226841_at MPEG1 4.58E−08 1.6484 1.8679.5 70.8-86.5 203474_at IQGAP2 5.06E−08 1.6275 2.51 79.2 70.6-86.2203766_s_at LMOD1 5.55E−08 1.58 2.97 78.5 69.8-85.6 214916_x_atLOC652128:IGHG1:IGHM:IGHV4- 5.75E−08 1.6352 3.1 79.3 70.6-86.331:LOC647189:IGHV1- 69:IGHA1:IL8:EXOC7:SIX6:IGHD: IGH@:IGHG3:C12orf32:ZCWPW2:IFI6:IGHG4:IGHA2: IGHG2:RAC1 226303_at PGM5 5.87E−08 1.6215 5.8779.1 70.4-86.2 225442_at DDR2 5.89E−08 1.562 2.61 78.3 69.4-85.4227561_at DDR2 5.89E−08 1.5604 2.61 78.2 69.4-85.5 202760_s_atAKAP2:PALM2:PALM2- 6.28E−08 1.6137 2.17 79 70.3-86.1 AKAP2 226694_atAKAP2:PALM2:PALM2- 6.28E−08 1.6143 2.17 79 70.2-86.1 AKAP2 204894_s_atAOC3 6.43E−08 1.556 2.92 78.2 69.4-85.4 203058_s_at PAPSS2 6.43E−081.6171 1.97 79.1 70.4-86.1 203060_s_at PAPSS2 6.43E−08 1.6159 1.97 7970.4-86.1 208763_s_at TSC22D3 7.22E−08 1.6098 2.76 79 70.2-86  222717_at SDPR 9.62E−08 1.5998 2.21 78.8 70.1-85.9 203680_at PRKAR2B1.05E−07 1.6759 2.1 79.9 71.2-86.8 201041_s_at DUSP1 1.06E−07 1.52952.44 77.8 68.9-85   209374_s_at LOC652128:IGHG1:IGHM:IGHV4- 1.12E−071.6333 3.1 79.3 70.6-86.3 31:LOC647189:IGHV1-69:IGHA1:IL8:EXOC7:SIX6:IGHD: IGH@:IGHG3:C12orf32:ZCWPW2:IFI6:IGHG4:IGHA2: IGHG2:RAC1 216491_x_atLOC652128:IGHG1:IGHM:IGHV4- 1.12E−07 1.6335 3.1 79.3 70.5-86.331:LOC647189:IGHV1- 69:IGHA1:IL8:EXOC7:SIX6:IGHD: IGH@:IGHG3:C12orf32:ZCWPW2:IFI6:IGHG4:IGHA2: IGHG2:RAC1 229831_at CNTN3 1.20E−07 1.6157 3.9379 70.2-86.1 235766_x_at RAB27A 1.22E−07 1.5984 1.79 78.8 70.1-85.9229070_at C6orf105 1.38E−07 1.6049 2.13 78.9 70.1-86   226654_at MUC121.53E−07 1.4559 4.89 76.7 67.7-84.1 202686_s_at AXL 1.59E−07 1.5758 1.7178.5 69.7-85.6 205403_at IL1R2 1.73E−07 1.5237 2.54 77.7 68.8-84.9211372_s_at IL1R2 1.73E−07 1.5229 2.54 77.7 68.7-85   205929_at GPA331.86E−07 1.7056 1.61 80.3 71.7-87.2 202069_s_at IDH3A 2.08E−07 1.56961.75 78.4 69.5-85.5 202350_s_at MATN2 2.11E−07 1.506 2.23 77.4 68.4-84.7212859_x_at NUTF2:MT1E:MT1M 2.14E−07 1.6442 2.41 79.4 70.8-86.4217546_at NUTF2:MT1E:MT1M 2.14E−07 1.645 2.41 79.5 70.7-86.5 216336_x_atNUTF2:MT1E:MT1M 2.14E−07 1.645 2.41 79.5 70.8-86.4 221667_s_at HSPB82.61E−07 1.514 3.85 77.5 68.6-84.8 217757_at A2M 2.72E−07 1.598 1.6478.8 70.1-85.9 216510_x_at LOC652128:IGHG1:IGHM:IGHV4- 2.80E−07 1.63463.1 79.3 70.6-86.4 31:LOC647189:IGHV1- 69:IGHA1:IL8:EXOC7:SIX6:IGHD:IGH@:IGHG3:C12orf32: ZCWPW2:IFI6:IGHG4:IGHA2: IGHG2:RAC1 223343_atNYD-SP21:MS4A7 2.92E−07 1.5396 2.27 77.9 69.1-85.1 202620_s_at PLOD23.06E−07 1.5551 2.33 78.2 69.3-85.4 207245_at UGT2B17 3.75E−07 1.47964.88 77 68.1-84.5 210139_s_at PMP22 3.97E−07 1.5183 2.23 77.6 68.7-84.9204938_s_at PLN 4.14E−07 1.5454 2.01 78 69.1-85.2 204939_s_at PLN4.14E−07 1.5425 2.01 78 69.1-85.2 204940_at PLN 4.14E−07 1.5436 2.01 7869.1-85.2 203951_at CNN1 4.77E−07 1.4324 4.56 76.3 67.3-83.8 202746_atITM2A 5.27E−07 1.4988 2.77 77.3 68.4-84.6 221584_s_at KCNMA1 6.86E−071.4959 2.37 77.3 68.4-84.6 241994_at XDH 8.13E−07 1.4709 2.03 76.967.9-84.3 209621_s_at PDLIM3 8.20E−07 1.4805 2.38 77   68-84.4204326_x_at LOC645652:MT1X 9.84E−07 1.4427 4.35 76.5 67.4-83.9208581_x_at LOC645652:MT1X 9.84E−07 1.4397 4.35 76.4 67.5-83.9201616_s_at CALD1 1.02E−06 1.4583 3.29 76.7 67.8-84.1 201617_x_at CALD11.02E−06 1.4617 3.29 76.8 67.7-84.1 212077_at CALD1 1.02E−06 1.4581 3.2976.7 67.8-84.1 225782_at MSRB3 1.20E−06 1.4747 2.24 77   68-84.3209436_at SPON1 1.46E−06 1.4849 1.88 77.1 68.1-84.4 223623_at C2orf401.69E−06 1.416 2.97 76.1   67-83.5 218087_s_at SORBS1:KIAA0894 2.18E−061.4259 2.54 76.2 67.3-83.7 222513_s_at SORBS1:KIAA0894 2.18E−06 1.42632.54 76.2 67.2-83.7 224990_at C4orf34 2.55E−06 1.3853 1.95 75.666.5-83.1 203131_at FIP1L1:PDGFRA 2.94E−06 1.4845 1.37 77.1 68.2-84.5203638_s_at FGFR2 3.55E−06 1.5287 1.31 77.8 68.9-85   201957_atPPP1R12B:LOC731632 4.26E−06 1.3611 2.21 75.2 66.2-82.8 217967_s_atFAM129A 4.59E−06 1.4131 1.8 76   67-83.5 210809_s_at POSTN 4.94E−061.3954 2.25 75.7 66.7-83.2 226302_at ATP8B1 5.73E−06 1.313 1.67 74.465.3-82.1 238750_at CCL28 6.01E−06 1.4932 1.53 77.2 68.3-84.6 226103_atNEXN 6.83E−06 1.3666 2.23 75.3 66.2-82.8 209101_at CTGF 6.96E−06 1.47741.3 77 68.1-84.4 229254_at MFSD4 7.19E−06 1.3235 2.12 74.6 65.4-82.3219087_at ASPN 7.45E−06 1.3249 2.74 74.6 65.5-82.3 209457_at DUSP58.60E−06 1.3336 1.91 74.8 65.7-82.4 221541_at CRISPLD2 9.24E−06 1.36641.64 75.3 66.2-82.9 206377_at FOXF2 9.50E−06 1.3032 2.08 74.3 65.1-82  207392_x_at UGT2B11:LOC728160:UGT2B15, 9.73E−06 1.3478 5.72 75 65.8-82.6UGT2B11:LOC728160:UGT2B15 202274_at ACTG2 1.07E−05 1.4015 1.82 75.866.8-83.4 227522_at CMBL 1.09E−05 1.3588 1.58 75.2   66-82.8 212192_atKCTD12 1.44E−05 1.3659 1.36 75.3 66.2-82.8 227727_at MRGPRF 1.52E−051.2965 2.99 74.2 65-82 234987_at C20orf118 1.75E−05 1.4278 1.3 76.267.3-83.7 209656_s_at TMEM47 1.86E−05 1.2983 2.02 74.2 65.1-82  212265_at QKI 1.93E−05 1.3443 1.31 74.9 65.9-82.6 228232_s_at VSIG22.01E−05 1.2957 2.05 74.1   65-81.9 200799_at HSPA1A, HSPA1A 2.16E−051.272 2.41 73.8 64.6-81.6 218312_s_at ZNF447 3.05E−05 1.107 1.39 7161.6-79.1 230264_s_at AP1S2 3.39E−05 1.2546 1.92 73.5 64.3-81.4224840_at FKBP5 3.41E−05 1.2371 1.71 73.2 63.9-81.1 209948_at KCNMB13.74E−05 1.2181 2.66 72.9 63.6-80.8 201426_s_at VIM 4.15E−05 1.2221 1.8672.9 63.7-80.8 227826_s_at SORBS2 4.23E−05 1.3017 2.1 74.2 65.1-82  227827_at SORBS2 4.23E−05 1.3015 2.1 74.2 65.1-82   225728_at SORBS24.23E−05 1.3015 2.1 74.2 65.1-82   238751_at SORBS2 4.23E−05 1.3019 2.174.2 65.1-82   228202_at C6orf204 4.90E−05 1.2062 2.07 72.7 63.5-80.6220645_at FAM55D 5.67E−05 1.1786 3.48 72.2   63-80.2 224560_at TIMP26.40E−05 1.2304 1.82 73.1 63.9-80.9 231579_s_at TIMP2 6.40E−05 1.22861.82 73 63.8-81   208788_at ELOVL5 8.15E−05 1.1804 2.05 72.2   63-80.2200974_at ACTA2 1.00E−04 1.2299 1.81 73.1 63.8-81   202388_at RGS20.0001 1.1604 1.94 71.9 62.7-80   206461_x_atMT1A:MT1H:LOC645745:LOC727730 0.0001 1.189 4.55 72.4 63.2-80.4208747_s_at C1S:PRB1:PRB2, C1S:PRB2:PRB1 0.0001 1.2884 1.61 74 64.9-81.9208791_at CLU 0.0001 1.2303 1.42 73.1 63.9-80.9 208792_s_at CLU 0.00011.2302 1.42 73.1 63.9-81   212185_x_at NUTF2:LOC441019:MT2A:MT1M, 0.00011.1894 1.89 72.4 63.1-80.3 NUTF2:LOC441019:MT2A: MT1M 222043_at CLU0.0001 1.2306 1.42 73.1 63.9-81   227099_s_at LOC387763 0.0001 1.19631.36 72.5 63.2-80.5 202766_s_at FBN1 0.0002 1.1359 1.93 71.5 62.2-79.6204745_x_at NUTF2:MT1G 0.0002 1.0888 2.66 70.7 61.3-78.9 218418_s_atANKRD25 0.0002 1.1139 1.56 71.1 61.9-79.3 201058_s_at MYL9 0.0003 1.1312.18 71.4 62.1-79.5 205547_s_at TAGLN 0.0003 1.0914 2.12 70.7 61.4-78.9205935_at FOXF1 0.0004 1.1743 1.28 72.1 62.9-80.1 208450_at LGALS20.0004 1.0845 3.07 70.6 61.4-78.8 203748_x_at RBMS1 0.0005 1.1435 1.5571.6 62.3-79.7 207266_x_at RBMS1 0.0005 1.1428 1.55 71.6 62.4-79.7209868_s_at RBMS1 0.0005 1.1437 1.55 71.6 62.3-79.7 225269_s_at RBMS10.0005 1.1446 1.55 71.6 62.3-79.6 212158_at SDC2 0.0006 1.0977 1.39 70.861.6-79.1 209209_s_at PLEKHC1 0.0007 1.0309 1.82 69.7 60.3-77.9209210_s_at PLEKHC1 0.0007 1.0325 1.82 69.7 60.3-78   205554_s_atACTB:DNASE1L3 0.0007 1.0979 1.5 70.8 61.4-78.9 202283_at SERPINF1 0.00091.0003 1.47 69.2 59.8-77.5 209496_at RARRES2:LOC648925 0.0009 1.0318 1.669.7 60.3-77.9 224352_s_at CFL2 0.0009 1.0586 1.75 70.2 60.8-78.4224663_s_at CFL2 0.0009 1.0575 1.75 70.2 60.8-78.4 214433_s_at SELENBP10.0009 1.0574 1.7 70.1 60.8-78.3 212592_at ENAM 0.0011 1.0024 2.58 69.259.8-77.5 213629_x_at MT1F 0.0012 0.9664 2.2 68.6 59.2-76.9 217165_x_atMT1F 0.0012 0.9649 2.2 68.5 59.2-76.9 203645_s_at CD163 0.0013 1.02311.9 69.6   60-77.9 215049_x_at CD163 0.0013 1.0215 1.9 69.5 60.1-77.8206641_at TNFRSF17 0.0015 1.0206 2.08 69.5 60.1-77.8 227235_at GUCY1A30.0015 1.0116 2.69 69.4 59.8-77.6 229530_at GUCY1A3 0.0015 1.0115 2.6969.3   60-77.6 212097_at CAV1 0.0016 1.0199 1.58 69.5 60.1-77.7200884_at CKB 0.0019 0.9758 2.27 68.7 59.2-77   202133_at WWTR1 0.0020.9917 1.48 69 59.5-77.4 204607_at HMGCS2 0.0022 0.8777 2.67 6757.5-75.5 218559_s_at MAFB 0.0034 0.9595 1.66 68.4   59-76.8 201061_s_atSTOM 0.0035 1.0165 1.21 69.4   60-77.7 201743_at CD14 0.0035 0.9627 1.5868.5 59.1-76.9 204895_x_at MUC4:TAF5L:LOC650855:LOC645744 0.0039 1.04481.2 69.9 60.6-78.2 217109_at MUC4:TAF5L:LOC650855:LOC645744 0.00391.0458 1.2 69.9 60.6-78.1 217110_s_at MUC4:TAF5L:LOC650855:LOC6457440.0039 1.0453 1.2 69.9 60.5-78.2 203382_s_at APOE 0.0044 0.9388 1.5668.1 58.7-76.5 206664_at SI 0.0054 0.9293 2.79 67.9 58.4-76.3 242447_atLOC285382 0.0058 0.7401 1.26 64.4 54.9-73.2 209312_x_at HLA-DRB1:HLA-0.0063 1.0636 1.51 70.3 60.9-78.5 DRB6:LOC731247:LOC730415:HLA-DRB4:HLA- DRB5:HLA- DRB3:LOC651845 215193_x_at HLA-DRB1:HLA- 0.00631.0646 1.51 70.3 60.9-78.5 DRB6:LOC731247:LOC730415: HLA-DRB4:HLA-DRB5:HLA- DRB3:LOC651845 224694_at ANTXR1 0.0071 0.9531 1.29 68.358.8-76.7 226811_at FAM46C 0.0085 0.9163 1.38 67.7 58.1-76.1 201150_s_atTIMP3 0.0091 0.9049 1.81 67.5 57.9-76   226682_at LOC283666 0.00990.7784 1.22 65.1 55.7-73.8 218468_s_at GREM1 0.0106 0.8585 3.03 66.657.2-75.2 218469_at GREM1 0.0106 0.8579 3.03 66.6 57.1-75.2 203240_atFCGBP:LOC651441:LOC652599 0.0121 0.7868 1.99 65.3 55.8-73.9 211538_s_atHSPA2 0.0123 0.8916 1.43 67.2 57.7-75.7 212091_s_at COL6A1 0.0126 0.8481.45 66.4 56.9-74.9 213428_s_at COL6A1 0.0126 0.8474 1.45 66.4 56.9-74.9226051_at SELM 0.0133 0.8606 1.32 66.7 57.1-75.1 200859_x_at FLNA:WTAP0.0157 0.7975 1.59 65.5 55.9-74   213746_s_at FLNA:WTAP 0.0157 0.79591.59 65.5   56-74.2 214752_x_at FLNA:WTAP 0.0157 0.798 1.59 65.5  56-74.1 204570_at COX7A1 0.0161 0.8622 1.32 66.7 57.2-75.2 203729_atEMP3 0.0164 0.8043 1.41 65.6 56.1-74.3 223597_at ITLN1 0.021 0.7148 2.5464 54.4-72.7 227735_s_at C10orf99 0.0218 0.7254 1.76 64.2 54.6-72.9227736_at C10orf99 0.0218 0.7259 1.76 64.2 54.6-72.9 200621_at CSRP10.023 0.7246 1.39 64.1 54.6-72.9 204897_at PTGER4:LOC730002:LOC7308820.0237 0.8114 1.41 65.8 56.2-74.4 204083_s_at PPIL5:TPM2 0.026 0.75311.53 64.7 55.2-73.4 211643_x_at HLA-C:HLA- 0.0268 0.9237 1.24 67.858.3-76.3 B:LOC730410:LOC652614:LOC732037 211644_x_at HLA-C:HLA- 0.02680.9229 1.24 67.8 58.3-76.2 B:LOC730410:LOC652614:LOC732037 214768_x_atHLA-C:HLA- 0.0268 0.9245 1.24 67.8 58.3-76.3B:LOC730410:LOC652614:LOC732037 226147_s_at PIGR 0.0278 0.7282 1.59 64.254.6-73   229659_s_at PIGR 0.0278 0.7253 1.59 64.2 54.7-72.9 201300_s_atPRNP 0.0288 0.7985 1.24 65.5   56-74.1 210133_at CCL11 0.0361 0.85341.32 66.5   57-75.1 225353_s_at C1QC 0.0391 0.7457 1.36 64.5   55-73.2201289_at CYR61 0.0425 0.7849 1.47 65.3 55.8-73.9 210764_s_at CYR610.0425 0.7836 1.47 65.2 55.6-73.9 200986_at SERPING1 0.0503 0.7672 1.4464.9 55.4-73.6 204122_at TYROBP:ZNF160 0.053 0.8181 1.17 65.9 56.4-74.5201667_at GJA1 0.0561 0.784 1.76 65.2 55.7-73.9 208789_at PTRF 0.06240.736 1.5 64.4 54.8-73.1 210107_at CLCA1 0.0681 0.7868 1.61 65.355.7-73.9 200665_s_at SPARC 0.0684 0.6714 1.45 63.1 53.6-72.1 212667_atSPARC 0.0684 0.6732 1.45 63.2 53.6-71.9 211964_at COL4A2 0.0738 0.70641.32 63.8 54.2-72.6 201858_s_at PRG1 0.0972 0.5559 1.25 60.9 51.3-69.9201859_at PRG1 0.0972 0.5563 1.25 61 51.4-69.9 228241_at BCMP11 0.1020.4028 1.28 58 48.4-67.1 217762_s_at RAB31 0.1041 0.8135 1.14 65.856.3-74.4 217764_s_at RAB31 0.1041 0.8132 1.14 65.8 56.2-74.5 202007_atNID1 0.105 0.7425 1.33 64.5   55-73.1 210495_x_at FN1 0.1121 0.5756 1.7361.3 51.8-70.2 211719_x_at FN1 0.1121 0.5767 1.73 61.3 51.8-70.2212464_s_at FN1 0.1121 0.5765 1.73 61.3 51.6-70.3 216442_x_at FN1 0.11210.5745 1.73 61.3 51.7-70.3 200600_at MSN 0.1499 0.7232 1.15 64.154.6-72.9 209138_x_at IGL@:LOC651536:LOC731062: 0.1551 0.681 1.26 63.353.8-72.2 CPVL:IGLV2-14:IGLV4- 3:IGLV3-25:IGLV3- 21:IL8:RPL14216984_x_at IGL@:LOC651536:LOC731062: 0.1551 0.6808 1.26 63.3 53.8-72.2CPVL:IGLV2-14:IGLV4- 3:IGLV3-25:IGLV3- 21:IL8:RPL14 217148_x_atIGL@:LOC651536:LOC731062: 0.1551 0.6808 1.26 63.3 53.9-72.1CPVL:IGLV2-14:IGLV4- 3:IGLV3-25:IGLV3- 21:IL8:RPL14 201069_at MMP20.1755 0.6214 1.24 62.2 52.6-71   202403_s_at COL1A2:LOC728628 0.18910.6508 1.9 62.8 53.2-71.5 202768_at FOSB 0.2076 0.6392 2.17 62.552.9-71.5 209116_x_at HBB 0.2357 0.6432 1.28 62.6 52.9-71.4 211696_x_atHBB 0.2357 0.6436 1.28 62.6 53.1-71.4 217232_x_at HBB 0.2357 0.6444 1.2862.6 53.1-71.5 205267_at POU2AF1 0.2389 0.6573 1.18 62.9 53.3-71.7201852_x_at COL3A1 0.2551 0.5524 1.35 60.9 51.3-69.8 211161_s_at COL3A10.2551 0.5509 1.35 60.9 51.3-69.9 215076_s_at COL3A1 0.2551 0.5513 1.3560.9 51.3-69.8 217378_x_at LOC391427 0.2627 0.2759 1.15 55.5 45.9-64.8223235_s_at SMOC2 0.2701 0.656 1.34 62.9 53.2-71.7 204673_atMUC5AC:LOC652741:MUC2 0.2802 0.8531 1.22 66.5   57-75.1 212414_s_atSep-06 0.3109 0.5714 1.21 61.2 51.7-70.2 201744_s_at LUM 0.3157 0.54251.54 60.7   51-69.7 202953_at C1QB 0.3668 0.4998 1.24 59.9 50.3-68.9209651_at TGFB1I1 0.4093 0.4932 1.35 59.7 50.2-68.8 212224_at ALDH1A10.4232 0.3525 1.4 57 47.4-66.2 211596_s_at LRIG1 0.4614 0.5988 1.26 61.852.2-70.7 218541_s_at C8orf4 0.475 0.4838 1.44 59.6   50-68.5 208894_atHLA-DRA:HLA-DQA1, HLA- 0.4823 0.3234 1.29 56.4 46.8-65.6 DRA:HLA-DQA1,HLA- DRA:HLA-DQA1 210982_s_at HLA-DRA:HLA-DQA1, HLA- 0.4823 0.3228 1.2956.4 46.8-65.6 DRA:HLA-DQA1, HLA- DRA:HLA-DQA1 227404_s_at EGR1 0.48510.5387 1.38 60.6   51-69.6 216401_x_at LOC652745 0.4864 0.1728 1.09 53.443.9-62.8 216207_x_at IGKV1D-13 0.5177 0.16 1.1 53.2 43.6-62.6 203477_atCOL15A1 0.6601 0.5385 1.22 60.6 51.1-69.7 211959_at IGFBP5 0.7663 0.35261.25 57 47.4-66.2 201105_at LGALS1 0.8555 0.4634 1.16 59.2 49.6-68.2201438_at COL6A3 0.8739 0.4434 1.2 58.8 49.2-67.8 212671_s_atHLA-DQA1:HLA- 0.8836 0.5398 1.28 60.6 51.1-69.7 DQA2, HLA-DQA1:LOC731682:HLA- DQA2 227725_at ST6GALNAC1 0.9452 0.2599 1.15 55.245.6-64.5 211990_at HLA-DPA1, HLA-DPA1 0.9664 0.417 1.39 58.3 48.7-67.4211991_s_at HLA-DPA1, HLA-DPA1 0.9664 0.4166 1.39 58.3 48.7-67.4217179_x_at IGLV1-44 0.9777 0.2852 1.07 55.7 46.1-65   234764_x_atIGLV1-44 0.9777 0.2847 1.07 55.7 46.1-64.9 224342_x_at IGLV1-44 0.97770.2848 1.07 55.7 46.1-65   215176_x_at NTN2L:IGKC:IGKV1- 0.9858 0.41671.43 58.3 48.6-67.3 5:GJB6:HLA-C 216576_x_at NTN2L:IGKC:IGKV1- 0.98580.4171 1.43 58.3 48.6-67.4 5:GJB6:HLA-C 201645_at TNC 0.9905 0.3687 1.0957.3 47.7-66.6 214414_x_at HBA1:HBA2, HBA1:HBA2 0.9979 0.4707 1.21 59.349.7-68.3 204018_x_at HBA1:HBA2, HBA1:HBA2 0.9979 0.4711 1.21 59.349.7-68.3 209458_x_at HBA1:HBA2, HBA1:HBA2 0.9979 0.4727 1.21 59.349.7-68.4 211699_x_at HBA1:HBA2, HBA1:HBA2 0.9979 0.4697 1.21 59.349.7-68.3 211745_x_at HBA1:HBA2, HBA1:HBA2 0.9979 0.4708 1.21 59.349.8-68.3 217414_x_at HBA1:HBA2, HBA1:HBA2 0.9979 0.469 1.21 59.349.7-68.4

TABLE 2 Gene Sens- Symbol ValidPS_DOWN Signif. FD

D.val5 FC Spec CI (95) GCNT2 935239-HuGene_st:225205-HuGene_st:1026280-2.16E−27 3.9513 13.36 97.6 94.2-99.2 HuGene_st:668101-HuGene_st:1099985-HuGene_st:698568-HuGene_st:134540- HuGene_st:697147-HuGene_st:250092-HuGene_st:611927-HuGene_st:972833- HuGene_st:168891-HuGene_st:990860-HuGene_st:109287-HuGene_st:322116-HuGene_st:231019-HuGene_st:211020_at:959570-HuGene_st:858764-HuGene_st:215593_at:820195-HuGene_st:239606_at:41059-HuGene_st:669940-HuGene_st:215595_x_at:230788_at GUCA2B276512-HuGene_st:1006871-HuGene_st:948364- 7.04E−25 3.6268 51.78 96.592.4-98.6 HuGene_st:46575-HuGene_st:207502_at:436788-HuGene_st:485636-HuGene_st:60132- HuGene_st:608718-HuGene_st:779511-HuGene_st:132431-HuGene_st:974232- HuGene_st:425596-HuGene_st:308287-HuGene_st:800088-HuGene_st:827119-HuGene_st:233789-HuGene_st:623623-HuGene_st GUCA1B 207003_at 7.32E−253.5625 10.7 96.3 91.9-98.5 CA4 636392-HuGene_st:206209_s_at:365396-1.73E−24 3.6291 10.41 96.5 92.4-98.7 HuGene_st:978203-HuGene_st:987169-HuGene_st:638557-HuGene_st:206208_at:1033858-HuGene_st:597808-HuGene_st:756864- HuGene_st:326439-HuGene_st:356096-HuGene_st:478435-HuGene_st:31642- HuGene_st:682778-HuGene_st:1006162-HuGene_st:673533-HuGene_st:491473- HuGene_st:822299-HuGene_st:871453-HuGene_st:209666-HuGene_st:465368- HuGene_st:354896-HuGene_st SLC4A4810103-HuGene_st:634869- 2.23E−23 3.6301 3.58 96.5 92.4-98.6HuGene_st:210739_x_at:211494_s_at:268096-HuGene_st:70822-HuGene_st:940785- HuGene_st:484105-HuGene_st:210738_s_at:203908_at:99375-HuGene_st:238833-HuGene_st:149464- HuGene_st:874564-HuGene_st:161948-HuGene_st:501640-HuGene_st:65687- HuGene_st:886057-HuGene_st:495376-HuGene_st:247215-HuGene_st:847550- HuGene_st:190252-HuGene_st:244077-HuGene_st:477911-HuGene_st:904959-HuGene_st:218417-HuGene_st:1554027_a_at AQP8486167-HuGene_st:126752-HuGene_st:93102- 2.98E−22 3.3311 10.82 95.290.3-97.9 HuGene_st:1090469-HuGene_st:980308-HuGene_st:107169-HuGene_st:829020- HuGene_st:1053234-HuGene_st:954102-HuGene_st:40331-HuGene_st:206784_at:990703-HuGene_st:459706-HuGene_st:863327- HuGene_st:965233-HuGene_st:459009-HuGene_st:180228-HuGene_st:944315- HuGene_st:814773-HuGene_st:810460-HuGene_st:228837-HuGene_st CA1 632246-HuGene_st:205950_s_at:382371-3.15E−22 3.3666 38.27 95.4 90.6-98   HuGene_st:1004598-HuGene_st:405837-HuGene_st:551543-HuGene_st:242482- HuGene_st:267733-HuGene_st:1074039-HuGene_st:107073-HuGene_st:485365- HuGene_st:254908-HuGene_st:257502-HuGene_st:333301-HuGene_st:180359- HuGene_st:696950-HuGene_st:588557-HuGene_st:381399-HuGene_st:495540- HuGene_st:384192-HuGene_st:205949_atABCG2 236197-HuGene_st:10623-HuGene_st:1005470- 1.09E−21 3.2599 31.5394.8 89.8-97.7 HuGene_st:140860-HuGene_st:492719-HuGene_st:417387-HuGene_st:113831- HuGene_st:507347-HuGene_st:944251-HuGene_st:175319-HuGene_st:784920- HuGene_st:709551-HuGene_st:136344-HuGene_st:689536-HuGene_st:209735_at:167748-HuGene_st:759590-HuGene_st:805222- HuGene_st:945575-HuGene_st:294363-HuGene_st:958524-HuGene_st:402982- HuGene_st:301335-HuGene_st OSTbeta552746-HuGene_st:57742-HuGene_st:461622- 6.23E−21 3.188 7.15 94.589.2-97.5 HuGene_st:965982-HuGene_st:413709-HuGene_st:230830_at:232719-HuGene_st:165400-HuGene_st:203597-HuGene_st:1025456- HuGene_st:625341-HuGene_st:881755-HuGene_st:490180-HuGene_st:113547- HuGene_st:605512-HuGene_st:179662-HuGene_st:280309-HuGene_st:647118-HuGene_st MGC13057926449-HuGene_st:317301-HuGene_st:834797- 6.94E−21 3.2029 3.18 94.589.3-97.5 HuGene_st:173388-HuGene_st:127937-HuGene_st:182395-HuGene_st:800172- HuGene_st:1041848-HuGene_st:93911-HuGene_st:810617-HuGene_st:1035428- HuGene_st:644866-HuGene_st:343402-HuGene_st:223754_at:228195_at:509933-HuGene_st CLDN23403960-HuGene_st:25144-HuGene_st:947653- 4.27E−20 3.0777 3.47 93.888.2-97.1 HuGene_st:228704_s_at:228706_s_at:320375-HuGene_st:441629:HuGene_st:367414-HuGene_st:855269-HuGene_st:228707_at:788659-HuGene_st:698816-HuGene_st:95789- HuGene_st:270197-HuGene_st:472976-HuGene_st:280539-HuGene_st:1056334-HuGene_st:516288-HuGene_st:579963-HuGene_st PKIB866170-HuGene_st:1055812-HuGene_st:264946- 5.94E−20 3.1232 3.28 94.188.7-97.3 HuGene_st:684057-HuGene_st:124791-HuGene_st:134561-HuGene_st:1026756- HuGene_st:468593-HuGene_st:1045852-HuGene_st:939917-HuGene_st:110205- HuGene_st:660721-HuGene_st:905229-HuGene_st:223551_at:610426-HuGene_st SEMA6D855766-HuGene_st:233882_s_at:543564- 6.07E−20 3.092 4.27 93.9 88.4-97.2HuGene_st:277987-HuGene_st:1075165-HuGene_st:220574_at:732853-HuGene_st:410940-HuGene_st:384488-HuGene_st:1041056-HuGene_st:233801_s_at:535378-HuGene_st:477671-HuGene_st:626423-HuGene_st:101599- HuGene_st:714098-HuGene_st:301505-HuGene_st:53682-HuGene_st:177281- HuGene_st:596415-HuGene_st:244746_at:226492_at:699792-HuGene_st:73748-HuGene_st:692437-HuGene_st CLCA4220026_at:1000955-HuGene_st:215807- 1.25E−19 3.1922 16.3 94.5 89.2-97.5HuGene_st:108406-HuGene_st:538359- HuGene_st:366726-HuGene_st:727431-HuGene_st:240891-HuGene_st:485685- HuGene_st:205213-HuGene_st:476179-HuGene_st:283676-HuGene_st:933390- HuGene_st:601908-HuGene_st:844633-HuGene_st:846667-HuGene_st:99723- HuGene_st:376041-HuGene_st:71188-HuGene_st:261183-HuGene_st:498330-HuGene_st:500064-HuGene_st:785031-HuGene_st TP53INP2224836_at:294906-HuGene_st:857693- 1.45E−19 3.0229 3.78 93.5 87.8-96.9HuGene_st:852970-HuGene_st:594178- HuGene_st:868173-HuGene_st:353925-HuGene_st:212485-HuGene_st:804363- HuGene_st:778869-HuGene_st:427072-HuGene_st:451529-HuGene_st:808765- HuGene_st:205314-HuGene_st:415164-HuGene_st:1048358-HuGene_st MS4A12 220834_at:582400-HuGene_st:354845-2.13E−19 3.2962 7.15 95   90-97.8 HuGene_st:341876-HuGene_st:769180-HuGene_st:740541-HuGene_st:436753- HuGene_st:570027-HuGene_st:26519-HuGene_st:956581-HuGene_st:335315- HuGene_st:206721-HuGene_st:589444-HuGene_st:16629-HuGene_st:113533- HuGene_st:201614-HuGene_st:774878-HuGene_st:786494-HuGene_st:493550- HuGene_st:403871-HuGene_st:192686-HuGene_st:846528-HuGene_st:249799-HuGene_st TRPM6767074-HuGene_st:695352-HuGene_st:411125- 2.25E−19 3.0106 7.5 93.487.7-96.8 HuGene_st:221102_s_at:234864_s_at:240389_at:358229-HuGene_st:755964-HuGene_st:840301- HuGene_st:959234-HuGene_st:782639-HuGene_st:833079-HuGene_st:1066034- HuGene_st:678013-HuGene_st:249083-HuGene_st:143934-HuGene_st:159130- HuGene_st:486486-HuGene_st:185057-HuGene_st:878793-HuGene_st:133981-HuGene_st:224412_s_at:202194-HuGene_st XLKD1520080-HuGene_st:1091117-HuGene_st:943125- 3.60E−19 2.94 7.44 92.987.1-96.6 HuGene_st:444068-HuGene_st:648558-HuGene_st:346991-HuGene_st:1006205- HuGene_st:373107-HuGene_st:682535-HuGene_st:1083245-HuGene_st:863143- HuGene_st:820120-HuGene_st:1044561-HuGene_st:220037_s_at:541228-HuGene_st:220256-HuGene_st:289122-HuGene_st:219059_s_at:246683-HuGene_st:775976-HuGene_st:207399-HuGene_st:1052557-HuGene_st:92121-HuGene_st ADH1B1078343-HuGene_st:512808-HuGene_st:614446- 4.70E−19 3.0172 4.67 93.487.7-96.9 HuGene_st:910188-HuGene_st:422504-HuGene_st:731361-HuGene_st:209612_s_at:258079-HuGene_st:568239-HuGene_st:879930- HuGene_st:420417-HuGene_st:1025048-HuGene_st:908335-HuGene_st:654633- HuGene_st:947292-HuGene_st:1087125-HuGene_st:1004870-HuGene_st:209613_s_at:579636-HuGene_st:681018-HuGene_st:822774-HuGene_st PRDX6353187-HuGene_st:520885-HuGene_st:919334- 5.56E−19 2.8414 2.76 92.286.1-96.1 HuGene_st:646105-HuGene_st:390352-HuGene_st:200844_s_at:855125-HuGene_st:200845_s_at:54231-HuGene_st:612931-HuGene_st:837652-HuGene_st:538086- HuGene_st:796167-HuGene_st:208992-HuGene_st:39945-HuGene_st:489353- HuGene_st:963499-HuGene_st:376244-HuGene_st:297536-HuGene_st:495777-HuGene_st:1005253-HuGene_st:833460-HuGene_st CA2762141-HuGene_st:111686-HuGene_st:512916- 5.87E−19 2.9625 9.22 93.187.2-96.7 HuGene_st:9132-HuGene_st:995083-HuGene_st:209301_at:578483-HuGene_st:583428-HuGene_st:961832-HuGene_st:11748- HuGene_st:1056641-HuGene_st:545067-HuGene_st:952781-HuGene_st:689246- 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65.555.9-74.1 HuGene_st:445061-HuGene_st:11735- HuGene_st:1066792-HuGene_st:214752_x_at:213746_s_at:871038-HuGene_st:396236-HuGene_st:200859_x_at:786282-HuGene_st:136680-HuGene_st:50466- HuGene_st:955232-HuGene_st:588605-HuGene_st:40025-HuGene_st:1002306- HuGene_st:833338-HuGene_st:86435-HuGene_st:172457-HuGene_st COX7A1 386303-HuGene_st:354428-HuGene_st0.0161 0.8613 1.32 66.7 57.2-75.3 EMP3736604-HuGene_st:155271-HuGene_st:584704- 0.0164 0.8053 1.41 65.656.1-74.2 HuGene_st ITLN1 389198-HuGene_st:496499-HuGene_st:48547- 0.0210.7137 2.54 63.9 54.4-72.7 HuGene_st:552029-HuGene_st:126777-HuGene_st:223597_at:281671-HuGene_st:45052-HuGene_st:573120-HuGene_st:137624- HuGene_st:948945-HuGene_st:527196-HuGene_st:358648-HuGene_st:45640- HuGene_st:512550-HuGene_st:839317-HuGene_st:634036-HuGene_st:101083-HuGene_st:857541-HuGene_st:404069-HuGene_st C10orf99227735_s_at:563767-HuGene_st:963471- 0.0218 0.724 1.76 64.1 54.7-72.9HuGene_st:965947-HuGene_st:1081062- HuGene_st:354432-HuGene_st:602661-HuGene_st:227736_at:1009594-HuGene_st:969063-HuGene_st:77052-HuGene_st:483367- HuGene_st:50662-HuGene_st:738457-HuGene_st:69019-HuGene_st:215415- HuGene_st:1003926-HuGene_st:676577-HuGene_st:676855-HuGene_st:225297- HuGene_st:560897-HuGene_st:886384-HuGene_st:303754-HuGene_st CSRP1453033-HuGene_st:673637-HuGene_st:607761- 0.023 0.7234 1.39 64.154.6-72.9 HuGene_st:582630-HuGene_st:654799-HuGene_st:258474-HuGene_st:200621_at:1028504-HuGene_st:802909-HuGene_st:339914- HuGene_st:533385-HuGene_st:256461-HuGene_st:1043113-HuGene_st:72101- HuGene_st:105671-HuGene_st:339691-HuGene_st:108781-HuGene_st:133369- HuGene_st:614016-HuGene_st:629648-HuGene_st:81550-HuGene_st PTGER4450915-HuGene_st:1067155-HuGene_st:812085- 0.0237 0.8101 1.41 65.756.2-74.4 HuGene_st:1943-HuGene_st:109314-HuGene_st:204897_at:252442-HuGene_st:800125-HuGene_st:965220-HuGene_st:446764-HuGene_st:204896_s_at:23686-HuGene_st:548266-HuGene_st:392964-HuGene_st:986807- HuGene_st:619166-HuGene_st TPM2828216-HuGene_st:373854-HuGene_st:981165- 0.026 0.7539 1.53 64.755.2-73.4 HuGene_st:191586-HuGene_st:445912-HuGene_st:446500-HuGene_st:922931- HuGene_st:336603-HuGene_st:272114-HuGene_st:375166-HuGene_st:8388-HuGene_st:204083_s_at:544548-HuGene_st:945443-HuGene_st:628440-HuGene_st:763118- HuGene_st:538951-HuGene_st PIGR748831-HuGene_st:226147_s_at:166398- 0.0278 0.7282 1.59 64.2 54.7-73  HuGene_st:593192-HuGene_st:204213_at:557727-HuGene_st:229659_s_at:242106-HuGene_st:146237-HuGene_st:883137-HuGene_st:691362- HuGene_st:201991-HuGene_st:1045753-HuGene_st:589879-HuGene_st:1017162- HuGene_st:325979-HuGene_st:105903-HuGene_st:1063932-HuGene_st:207526- HuGene_st:566905-HuGene_st HLA-C754900-HuGene_st 0.0279 0.9253 1.24 67.8 58.3-76.2 PRNP178399-HuGene_st:201300_s_at:386578- 0.0288 0.798 1.24 65.5   56-74.2HuGene_st:783439-HuGene_st CCL11 495934-HuGene_st 0.0361 0.8547 1.3266.5 57.1-75   C1QC 137801-HuGene_st:851445-HuGene_st 0.0391 0.7457 1.3664.5 54.9-73.3 CYR61 736150-HuGene_st:385534-HuGene_st:48239- 0.04250.7875 1.47 65.3 55.7-73.9 HuGene_st:242630-HuGene_st SERPING1 NA 0.05030.7659 1.44 64.9 55.4-73.6 TYROBP NA 0.053 0.8176 1.17 65.9 56.3-74.5GJA1 NA 0.0561 0.7839 1.76 65.2 55.6-73.9 PTRF NA 0.0624 0.7354 1.5 64.354.8-73.1 CLCA1 NA 0.0681 0.7855 1.61 65.3 55.8-74 SPARC NA 0.06840.6702 1.45 63.1 53.5-71.9 COL4A2 NA 0.0738 0.7081 1.32 63.8 54.3-72.5RAB31 NA 0.1041 0.8159 1.14 65.8 56.3-74.4 NID1 NA 0.105 0.7428 1.3364.5 54.9-73.2 FN1 NA 0.1121 0.5769 1.73 61.3 51.7-70.2 MSN NA 0.14990.7215 1.15 64.1 54.6-72.9 MMP2 NA 0.1755 0.6219 1.24 62.2 52.5-71.2COL1A2 NA 0.1891 0.65 1.9 62.7 53.2-71.6 FOSB NA 0.2076 0.6389 2.17 62.552.9-71.4 HBB NA 0.2357 0.6434 1.28 62.6   53-71.5 POU2AF1 NA 0.23890.6564 1.18 62.9 53.3-71.7 COL3A1 NA 0.2551 0.5538 1.35 60.9 51.3-69.9SMOC2 NA 0.2701 0.6533 1.34 62.8 53.2-71.7 MUC2 NA 0.2802 0.8523 1.2266.5 57-75 Sep-06 NA 0.3109 0.5713 1.21 61.2 51.7-70.2 LUM NA 0.31570.5442 1.54 60.7 51.1-69.7 C1QB NA 0.3668 0.5005 1.24 59.9 50.4-69  TGFB1I1 NA 0.4093 0.4951 1.35 59.8 50.1-68.8 ALDH1A1 NA 0.4232 0.354 1.457 47.4-66.2 LRIG1 NA 0.4614 0.5998 1.26 61.8 52.2-70.7 C8orf4 NA 0.4750.483 1.44 59.5 49.9-68.5 EGR1 NA 0.4851 0.5374 1.38 60.6   51-69.6LOC652745 NA 0.4864 0.1722 1.09 53.4 43.8-62.8 IGKV1D- NA 0.5177 0.15971.1 53.2 43.7-62.5 13 COL15A1 NA 0.6601 0.54 1.22 60.6   51-69.6 IGFBP5NA 0.7663 0.3504 1.25 57 47.4-66.3 LGALS1 NA 0.8555 0.4626 1.16 59.149.5-68.3 COL6A3 NA 0.8739 0.4412 1.2 58.7 49.1-67.9 HLA- NA 0.90840.5417 1.28 60.7 51.1-69.6 DQA1 HLA-DRA NA 0.9084 0.5391 1.28 60.6  51-69.6 ST6GALNAC1 NA 0.9452 0.2594 1.15 55.2 45.6-64.5 HLA-DPA1 NA0.9664 0.4166 1.39 58.3 48.7-67.4 IGLV1-44 NA 0.9777 0.2865 1.07 55.746.1-64.9 TNC NA 0.9905 0.3682 1.09 57.3 47.7-66.5 HBA1 NA 0.9979 0.471.21 59.3 49.6-68.4 HBA2 NA 0.9979 0.4705 1.21 59.3 49.6-68.3

indicates data missing or illegible when filed

TABLE 3 TargetPS Symbol Signif. FDR D.val5 FC Sens-Spec CI (95)230788_at SPTLC3: GCNT2 2.1587E−27 3.9562 13.36 97.6 94.2-99.2228706_s_at CLDN23 4.2694E−20 3.0727 3.47 93.8 88.3-97.1 231120_x_atPKIB 5.9397E−20 3.1191 3.28 94.1 88.6-97.3 224412_s_at TRPM6 2.2514E−193.0115 7.5 93.4 87.7-96.8 220037_s_at XLKD1 3.5991E−19 2.9405 7.44 92.9 87-96.5 209613_s_at ADH1B: ADH1A 4.6957E−19 3.0158 4.67 93.4 87.7-96.9204719_at ABCA8 1.2559E−18 2.9171 6.82 92.8 86.8-96.5 231773_at ANGPTL11.4172E−17 2.7946 4.64 91.9 85.6-95.9 225575_at LIFR 2.4532E−17 2.77976.36 91.8 85.5-95.8 220812_s_at HHLA2 3.4739E−17 2.6718 10.02 90.984.4-95.2 211549_s_at HPGD 3.6502E−17 2.8451 3.21 92.3 86.1-96.1202920_at ANK2 2.5934E−16 2.6488 6.76 90.7 84.2-95.1 231925_at P2RY11.4091E−15 2.5329 3.6 89.7 82.8-94.4 207080_s_at PYY 3.5022E−15 2.478311.71 89.2 82.2-94  228885_at RPL24: LOC731365 1.2312E−14 2.5575 1.63 9083.1-94.6 228766_at CD36 6.2677E−14 2.4687 1.65 89.1 82.1-94  204931_atTCF21 2.5147E−13 2.3036 2.34 87.5 80.1-92.8 205433_at BCHE 3.1756E−132.2538 6.21 87 79.5-92.5 207980_s_at CITED2 5.2905E−13 2.2709 1.64 87.279.7-92.6 209170_s_at GPM6B 4.0429E−12 2.1588 3.59 86 78.1-91.6220376_at LRRC19 6.7548E−12 2.0763 4.51 85 77.1-90.9 228504_at No Symbol9.1926E−12 2.152 1.61 85.9 78.2-91.6 228854_at No Symbol 9.1926E−122.1538 1.61 85.9 78.2-91.6 235146_at No Symbol 9.1926E−12 2.1537 1.6185.9 78.2-91.6 221305_s_at UGT1A10: UGT1A7: UGT1A8: 1.0319E−11 2.06774.56 84.9 77.1-90.9 UGT1A1: UGT1A9: UGT1A6: UGT1A5: UGT1A3: UGT1A4203881_s_at DMD 5.0063E−11 2.0137 4.74 84.3 76.3-90.4 206637_at P2RY141.3104E−10 1.9836 2 83.9 75.8-90.1 214598_at CLDN8 2.9225E−10 1.862412.96 82.4 74.1-88.9 227529_s_at AKAP12 7.4077E−09 1.7434 2.83 80.872.3-87.5 219948_x_at LOC642329: UGT2A3 8.638E−09 1.741 4.89 80.872.3-87.6 222717_at SDPR 9.6207E−08 1.5993 2.21 78.8 70.1-85.9 229831_atCNTN3 1.1953E−07 1.6145 3.93 79 70.3-86.1 204940_at PLN 4.1416E−071.5439 2.01 78 69.2-85.2 227827_at SORBS2 4.2323E−05 1.3016 2.1 74.265.1-81.9 238751_at SORBS2 4.2323E−05 1.3015 2.1 74.2 65.1-82 209209_s_at PLEKHC1 0.0007 1.0304 1.82 69.7 60.3-78  206664_at SI 0.00540.9301 2.79 67.9 58.4-76.3

TABLE 4 Gene Symbol ValidPS_DOWN Signif. FDR D.val5 FC Sens-Spec CI (95)ANK2 314086-HuGene_st: 282874-HuGene_st: 382431- 2.59E−16 2.6515 6.7690.8 84.1-95.1 HuGene_st: 229308-HuGene_st: 779600-HuGene_st: 297624-HuGene_st: 385943-HuGene_st: 730140-HuGene_st: 442277- HuGene_st:699309-HuGene_st: 182816- HuGene_st: 202921_s_at: 799860-HuGene_st:868462- HuGene_st: 634421-HuGene_st: 571536-HuGene_st: 1050903-HuGene_st: 649509-HuGene_st: 239935-HuGene_st: 202920_at DMD945600-HuGene_st: 12596-HuGene_st: 434657- 5.01E−11 2.0162 4.74 84.376.3-90.4 HuGene_st: 676962-HuGene_st: 1020969-HuGene_st: 170680-HuGene_st: 855670-HuGene_st: 909848-HuGene_st: 134644- HuGene_st:887814-HuGene_st: 649184-HuGene_st: 110990- HuGene_st: 914217-HuGene_st:961622-HuGene_st: 514011- HuGene_st: 842792-HuGene_st: 445483-HuGene_st: 208086_s_at: 987362-HuGene_st: 997308- HuGene_st ABCA857305-HuGene_st: 111752-HuGene_st: 61357- 1.26E−18 2.9182 6.82 92.886.8-96.5 HuGene_st: 123451-HuGene_st: 740746-HuGene_st: 512280-HuGene_st: 389185-HuGene_st: 427721-HuGene_st: 346028- HuGene_st:224566-HuGene_st: 149653-HuGene_st: 680699- HuGene_st: 76772-HuGene_st:742091-HuGene_st: 423333- HuGene_st: 559944-HuGene_st: 341399-HuGene_st: 1565780_at: 863400-HuGene_st: 921748- HuGene_st:623719-HuGene_st: 204719_at: 123143- HuGene_st: 1077391-HuGene_st TCF21804657-HuGene_st: 106365-HuGene_st: 710514- 2.51E−13 2.3037 2.34 87.580.1-92.9 HuGene_st: 299556-HuGene_st: 608149-HuGene_st: 242233-HuGene_st: 655881-HuGene_st: 356773-HuGene_st: 788445- HuGene_st:709897-HuGene_st: 605488-HuGene_st: 652466- HuGene_st: 204931_at:830709-HuGene_st: 273418- HuGene_st: 1004754-HuGene_st:990861-HuGene_st: 238739- HuGene_st: 836241-HuGene_st: 110045-HuGene_st: 229529_at: 1001969-HuGene_st PLN 204938_s_at:418214-HuGene_st: 769837-HuGene_st: 603329- 4.14E−07 1.5399 2.01 77.969.2-85.2 HuGene_st: 1048096-HuGene_st: 944510-HuGene_st: 430402-HuGene_st: 86633-HuGene_st: 795093-HuGene_st: 377757- HuGene_st:770145-HuGene_st: 920628-HuGene_st: 594048- HuGene_st: 800583-HuGene_st:204939_s_at: 556723- HuGene_st: 818339-HuGene_st: 175524-HuGene_st:498924- HuGene_st: 204940_at BCHE 228090-HuGene_st: 752051-HuGene_st:800167- 3.18E−13 2.2544 6.21 87 79.4-92.5 HuGene_st: 221362-HuGene_st:155900-HuGene_st: 717363- HuGene_st: 536584-HuGene_st: 146780-HuGene_st:302487- HuGene_st: 508472-HuGene_st: 516293-HuGene_st: 968992-HuGene_st: 666625-HuGene_st: 923158-HuGene_st P2RY14 528057-HuGene_st:780310-HuGene_st: 235178- 1.31E−10 1.9805 2 83.9 75.9-90  HuGene_st:352954-HuGene_st: 699489-HuGene_st: 38001- HuGene_st: 637791-HuGene_st:25606-HuGene_st: 40647- HuGene_st: 896487-HuGene_st: 672149-HuGene_st:863820- HuGene_st: 352427-HuGene_st: 632821-HuGene_st: 116148-HuGene_st: 561792-HuGene_st: 840910-HuGene_st: 296420- HuGene_st:974643-HuGene_st: 206637_at PYY 656845-HuGene_st: 816022-HuGene_st:633572- 3.50E−15 2.4828 11.71 89.3 82.2-94  HuGene_st: 20355-HuGene_st:240779-HuGene_st: 638358- HuGene_st: 879780- HuGene_st: 207080_s_at:211253_x_at: 368591-HuGene_st CITED2 125201-HuGene_st: 410723-HuGene_st:463405- 5.29E−13 2.269 1.64 87.2 79.7-92.6 HuGene_st: 401168-HuGene_st:1012057-HuGene_st: 235057- HuGene_st: 361772-HuGene_st: 207980_s_at:1091907- HuGene_st: 985355-HuGene_st: 175990- HuGene_st: 227287_at:48433-HuGene_st: 209357_at: 477746- HuGene_st: 243264-HuGene_st:904401-HuGene_st: 328536- HuGene_st: 1095110-HuGene_st: 89784-HuGene_st:206734- HuGene_st: 927615-HuGene_st GPM6B 599862-HuGene_st:754598-HuGene_st: 503642- 4.04E−12 2.1547 3.59 85.9 78.2-91.7 HuGene_st:224935-HuGene_st: 754449-HuGene_st: 577489- HuGene_st:1073242-HuGene_st: 560873-HuGene_st: 1003662- HuGene_st:430217-HuGene_st: 903323-HuGene_st: 231962- HuGene_st: 244945-HuGene_st:562460-HuGene_st: 583561- HuGene_st: 209168_at PLEKHC1 831786-HuGene_st:88016-HuGene_st: 1087035- 7.00E−04 1.0307 1.82 69.7 60.4-78  HuGene_st:530331-HuGene_st: 209209_s_at: 184398- HuGene_st: 904923-HuGene_st:193550-HuGene_st: 468805- HuGene_st: 104495-HuGene_st: 604317-HuGene_st:501652- HuGene_st: 118096-HuGene_st: 321532-HuGene_st: 675257-HuGene_st: 79496-HuGene_st: 590867-HuGene_st: 147248- HuGene_st:627402-HuGene_st: 377514-HuGene_st ADH1B 1078343-HuGene_st:512808-HuGene_st: 614446- 4.70E−19 3.0174 4.67 93.4 87.7-96.9 HuGene_st:910188-HuGene_st: 422504-HuGene_st: 731361- HuGene_st: 209612_s_at:258079-HuGene_st: 568239- HuGene_st: 879930-HuGene_st: 420417-HuGene_st:1025048- HuGene_st: 908335-HuGene_st: 654633-HuGene_st: 947292-HuGene_st: 1087125-HuGene_st: 1004870- HuGene_st: 209613_s_at:579636-HuGene_st: 681018- HuGene_st: 822774-HuGene_st XLKD1520080-HuGene_st: 1091117-HuGene_st: 943125- 3.60E−19 2.9461 7.44 9387.1-96.6 HuGene_st: 444068-HuGene_st: 648558-HuGene_st: 346991-HuGene_st: 1006205-HuGene_st: 373107-HuGene_st: 682535- HuGene_st:1083245-HuGene_st: 863143-HuGene_st: 820120- HuGene_st:1044561-HuGene_st: 220037_s_at: 541228- HuGene_st: 220256-HuGene_st:289122- HuGene_st: 219059_s_at: 246683-HuGene_st: 775976- HuGene_st:207399-HuGene_st: 1052557-HuGene_st: 92121- HuGene_st LRRC19177641-HuGene_st: 1070020-HuGene_st: 1055140- 6.75E−12 2.0779 4.51 85.177.1-91  HuGene_st: 525999-HuGene_st: 937256-HuGene_st: 620791-HuGene_st: 891251-HuGene_st: 707559-HuGene_st: 892056- HuGene_st:764919-HuGene_st: 382143-HuGene_st: 52584- HuGene_st: 920414-HuGene_st:1028155-HuGene_st: 755055- HuGene_st: 678651-HuGene_st:1080156-HuGene_st: 530282- HuGene_st: 523877-HuGene_st:335198-HuGene_st: 787709- HuGene_st: 153175-HuGene_st: 220376_at SDPR878908-HuGene_st: 781527-HuGene_st: 331976- 9.62E−08 1.6036 2.21 78.9 70-85.9 HuGene_st: 238150-HuGene_st: 306039-HuGene_st: 535903-HuGene_st: 302361-HuGene_st: 1005813-HuGene_st: 71118- HuGene_st:992629-HuGene_st: 218711_s_at: 293110- HuGene_st: 779040-HuGene_st:222717_at: 970479- HuGene_st: 581654-HuGene_st TRPM6 767074-HuGene_st:695352-HuGene_st: 411125- 2.25E−19 3.0111 7.5 93.4 87.7-96.8 HuGene_st:221102_s_at: 234864_s_at: 240389_at: 358229- HuGene_st:755964-HuGene_st: 840301-HuGene_st: 959234- HuGene_st: 782639-HuGene_st:833079-HuGene_st: 1066034- HuGene_st: 678013-HuGene_st:249083-HuGene_st: 143934- HuGene_st: 159130-HuGene_st: 486486-HuGene_st:185057- HuGene_st: 878793-HuGene_st: 133981- HuGene_st: 224412_s_at:202194-HuGene_st LIFR 275506-HuGene_st: 323055-HuGene_st: 444251-2.45E−17 2.7814 6.36 91.8 85.5-95.8 HuGene_st: 1056178-HuGene_st:398104-HuGene_st: 917434- HuGene_st: 1044918-HuGene_st:167500-HuGene_st: 423760- HuGene_st: 837336-HuGene_st: 321505-HuGene_st:918321- HuGene_st: 252278-HuGene_st: 884504-HuGene_st: 124845-HuGene_st: 499777-HuGene_st: 969722-HuGene_st: 709439- HuGene_st:611505-HuGene_st: 227771_at: 287217- HuGene_st: 205876_at: 225571_at:229185_at: 233367_at: 1093011-HuGene_st AKAP12 212419-HuGene_st:231067_s_at: 379659- 7.41E−09 1.7456 2.83 80.9 72.4-87.6 HuGene_st:1010338-HuGene_st: 1075094-HuGene_st: 42401- HuGene_st:522584-HuGene_st: 480972-HuGene_st: 948623- HuGene_st: 701945-HuGene_st:276784-HuGene_st: 64858- HuGene_st: 210517_s_at: 874382-HuGene_st:909976- HuGene_st: 182037-HuGene_st: 417182-HuGene_st: 722881- HuGene_stCLDN23 403960-HuGene_st: 25144-HuGene_st: 947653- 4.27E−20 3.0748 3.4793.8 88.2-97.1 HuGene_st: 228704_s_at: 228706_s_at: 320375- HuGene_st:441629-HuGene_st: 367414-HuGene_st: 855269- HuGene_st: 228707_at:788659-HuGene_st: 698816- HuGene_st: 95789-HuGene_st: 270197-HuGene_st:472976- HuGene_st: 280539-HuGene_st: 1056334-HuGene_st: 516288-HuGene_st: 579963-HuGene_st CD36 392196-HuGene_st: 274514-HuGene_st:477005- 6.27E−14 2.4696 1.65 89.2 82.1-94  HuGene_st: 691585-HuGene_st:872909-HuGene_st: 543050- HuGene_st: 603343-HuGene_st: 514557-HuGene_st:296850- HuGene_st: 945913-HuGene_st: 495755- HuGene_st: 206488_s_at:1035854-HuGene_st: 887301- HuGene_st: 836370-HuGene_st: 209555_s_at:939919- HuGene_st: 507440-HuGene_st: 151788-HuGene_st: 146280-HuGene_st: 360545-HuGene_st: 1051486- HuGene_st: 228766_at:512885-HuGene_st RPL24 1559655_at: 1559656_a_at: 228885_at 1.23E−142.5568 1.63 89.9 83.1-94.6 GCNT2 935239-HuGene_st: 225205-HuGene_st:1026280- 2.16E−27 3.9536 13.36 97.6 94.1-99.2 HuGene_st:668101-HuGene_st: 1099985-HuGene_st: 698568- HuGene_st:134540-HuGene_st: 697147-HuGene_st: 250092- HuGene_st: 611927-HuGene_st:972833-HuGene_st: 168891- HuGene_st: 990860-HuGene_st: 109287-HuGene_st:322116- HuGene_st: 231019-HuGene_st: 211020_at: 959570- HuGene_st:858764-HuGene_st: 215593_at: 820195- HuGene_st: 239606_at:41059-HuGene_st: 669940- HuGene_st: 215595_x_at: 230788_at PKIB866170-HuGene_st: 1055812-HuGene_st: 264946- 5.94E−20 3.1204 3.28 94.188.6-97.3 HuGene_st: 684057-HuGene_st: 124791-HuGene_st: 134561-HuGene_st: 1026756-HuGene_st: 468593-HuGene_st: 1045852- HuGene_st:939917-HuGene_st: 110205-HuGene_st: 660721- HuGene_st: 905229-HuGene_st:223551_at: 610426-HuGene_st ANGPTL1 572942-HuGene_st: 891312-HuGene_st:953040- 1.42E−17 2.7964 4.64 91.9 85.6-95.9 HuGene_st: 232844-HuGene_st:145730-HuGene_st: 142205- HuGene_st: 227771-HuGene_st: 80584-HuGene_st:982090- HuGene_st: 999640-HuGene_st: 672931-HuGene_st: 148578-HuGene_st: 224339_s_at: 1046706- HuGene_st: 239183_at: 155600-HuGene_st:284674- HuGene_st: 231773_at: 818064-HuGene_st: 978991- HuGene_st:728775-HuGene_st SI 9605-HuGene_st: 514814-HuGene_st: 809314- 5.40E−030.9299 2.79 67.9 58.4-76.4 HuGene_st: 576613-HuGene_st: 45502-HuGene_st:369676- HuGene_st: 438636-HuGene_st: 267204-HuGene_st: 326716-HuGene_st: 897825-HuGene_st: 377666-HuGene_st: 519273- HuGene_st:325741-HuGene_st: 245381-HuGene_st: 108368- HuGene_st: 464198-HuGene_st:679193-HuGene_st: 168180- HuGene_st HPGD 291863-HuGene_st:375608-HuGene_st: 793406- 3.65E−17 2.8462 3.21 92.3 86.2-96.1 HuGene_st:436293-HuGene_st: 75568- HuGene_st: 211549_s_at: 684728-HuGene_st:674596- HuGene_st: 527856-HuGene_st: 329920-HuGene_st: 748432-HuGene_st: 259392-HuGene_st: 769902-HuGene_st: 620673- HuGene_st:450707-HuGene_st: 203913_s_at: 304752- HuGene_st: 447604-HuGene_st:170968-HuGene_st: 852359- HuGene_st: 836377-HuGene_st: 242733_at:243846- HuGene_st: 136281-HuGene_st: 203914_x_at: 1018006- 211548_s_at:288252-HuGene_st CLDN8 1018006-HuGene_st: 190634-HuGene_st: 590280-2.92E−10 1.8639 12.96 82.4 74.1-88.9 HuGene_st: 186468-HuGene_st:954438-HuGene_st: 428391- HuGene_st: 480543-HuGene_st: 944337-HuGene_st:179725- HuGene_st: 508584-HuGene_st: 1009114-HuGene_st: 948216-HuGene_st: 658285-HuGene_st: 1022600-HuGene_st: 737498- HuGene_st:470015-HuGene_st: 103315-HuGene_st: 699348- HuGene_st: 89877-HuGene_st:56937-HuGene_st: 862663- HuGene_st: 504945-HuGene_st: 214598_at UGT2A3149647-HuGene_st: 860083-HuGene_st: 922544- 8.64E−09 1.7422 4.89 80.872.3-87.5 HuGene_st: 244206-HuGene_st: 503323-HuGene_st: 353576-HuGene_st: 603619-HuGene_st: 787458-HuGene_st: 219796- HuGene_st:333564-HuGene_st: 257402-HuGene_st: 366699- HuGene_st: 461685-HuGene_st:891681-HuGene_st: 644952- HuGene_st: 621618-HuGene_st: 737617-HuGene_st:88682- HuGene_st: 529761-HuGene_st: 895203-HuGene_st: 658594- HuGene_st:455115-HuGene_st HHLA2 371335-HuGene_st: 978721-HuGene_st: 1065567-3.47E−17 2.6743 10.02 90.9 84.3-95.2 HuGene_st: 282548-HuGene_st:240410-HuGene_st: 170899- HuGene_st: 947848-HuGene_st: 438234-HuGene_st: 220812_s_at: 927495-HuGene_st: 351364- HuGene_st: 234673_at:993142-HuGene_st: 1009637- HuGene_st: 335000-HuGene_st:285313-HuGene_st: 533646- HuGene_st: 234624_at: 458597-HuGene_st:104838- HuGene_st: 26687-HuGene_st: 258409-HuGene_st: 493304- HuGene_st:378019-HuGene_st: 576796-HuGene_st UGT1A8 116025-HuGene_st:6488-HuGene_st: 881135- 1.32E−11 2.0703 4.56 85 77.1-90.9 HuGene_st:230953_at: 221304_at: 221305_s_at: 511516- HuGene_st: 594963-HuGene_st:396121-HuGene_st: 123777- HuGene_st: 1016481-HuGene_st: 204532_x_at:683377- HuGene_st: 1055169-HuGene_st: 1035103- HuGene_st:1088102-HuGene_st: 207126_x_at: 42874- HuGene_st: 215125_s_at:206094_x_at: 208596_s_at: 97211- HuGene_st: 1009861-HuGene_st:603368-HuGene_st: 232654_s_at: 625897-HuGene_st: 998604-HuGene_st CNTN3267567-HuGene_st: 782053-HuGene_st: 550157- 1.20E−07 1.6155 3.93 7970.3-86.1 HuGene_st: 541394-HuGene_st: 989173-HuGene_st: 15899-HuGene_st: 78622-HuGene_st: 339738-HuGene_st: 585282- HuGene_st:661814-HuGene_st: 360715-HuGene_st: 695033- HuGene_st: 483058-HuGene_st:555394-HuGene_st: 315011- HuGene_st: 905374-HuGene_st:1067212-HuGene_st: 557263- HuGene_st: 233502_at: 811729-HuGene_st:87414-HuGene_st P2RY1 628249-HuGene_st: 113454-HuGene_st: 627857-1.41E−15 2.5326 3.6 89.7 82.8-94.4 HuGene_st: 461281-HuGene_st:207455_at: 259065- HuGene_st: 797734-HuGene_st: 135788-HuGene_st: 42916-HuGene_st: 315405-HuGene_st: 340050-HuGene_st: 173225- HuGene_st:919818-HuGene_st: 591228-HuGene_st: 899117- HuGene_st: 785070-HuGene_st:286200-HuGene_st: 231925_at SORBS2 238751_at: 805920-HuGene_st 4.23E−051.3026 2.1 74.3 65.1-82 

TABLE 5 Normal Gene Blood MRC5 CaCo2 HCT116 HT29 SW480 CXCL12 Unmeth lowunmeth meth meth unmeth DF Low meth meth meth unmeth meth MAMDC2 Unmethunmeth meth unmeth unmeth meth CA4 unmeth unmeth meth meth meth unmethMT1M low low low meth low meth P2RY14 unmeth Low Meth Meth Unmeth MethGPM6B Low Low Low Meth Meth Meth ADAMDEC1 low Unmeth Meth Meth unmethmeth

TABLE 6 Probe Set ID Target Sequence 1 200600_attagtcttggggcaggatgattttggcctcattactttaccacccccacacctggaaagcatatactatattacaaaatgacattttgccaaaattattaatataagaagctttcagtattagtgatgtcatctgtcactataggtcatacaatccattcttaaagtacttgttatttgtttttattattactgtttgtcttctccccagggttcagtccctcaaggggccatcctgtcccaccatgcagtgccccctagcttagagcctccctcaattccccctggccaccaccccccactctgtgcctgaccttgaggagtcttgtgtgcattgctgtgaattagctcacttggtgatatgtcctatattggctaaattgaaacctggaattgtggggcaatctattaatagctgccttaaagtcagtaacttacccttagggaggctgggggaaaaggttagattttgtattcaggggttttttgtgtactttttgggtttttaaaaaattgtttttggaggggtttatgctcaatccatgt2 200621_atgatagcctcccactaggactgggaggagaataacccaggtcttaaggaccccaaagtcaggatgttgtttgatcttctcaaacatctagttccctgcttgatgggaggatcctaatgaaatacctgaaacatatattggcatttatcaatggctcaaatcttcatttatctctggccttaaccctggctcctgaggctgcggccagcagagcccaggccagggctctgttcttgccacacctgcttgatcctcagatgtggagggaggtaggcactgcctcagtcttcatccaaacacctttccctttgccctgagacctcagaatcttccctttaacccaagaccctgcctcttccactccacccttctccagggacccttagatcacatcactccacccctgccaggccccaggttaggaatagtggtgggaggaaggggaaagggctgggcctcaccgctcccagcaactgaaaggacaacactatctggagccacccactgaaagggctgcaggcatgggctgtac3 200665_s_atgttggttcaaacttttgggagcacggactgtcagttctctgggaagtggtcagcgcatcctgcagggcttctcctcctctgtcttttggagaaccagggctcttctcaggggctctagggactgccaggctgtttcagccaggaaggccaaaatcaagagtgagatgtagaaagttgtaaaatagaaaaagtggagttggtgaatcggttgttctttcctcacatttggatgattgtcataaggtttttagcatgttcctccttttcttcaccctcccctttgttcttctattaatcaagagaaacttcaaagttaatgggatggtcggatctcacaggctgagaactcgttcacctccaagcatttcatgaaaaagctgcttcttattaatcatacaaactctcaccatgatgtg4 200795_ataacactgcataacccgtttctttgaggagtgtgaccccaacaaggataagcacatcaccctgaaggagtggggccactgctttggaattaaagaagaggacatagatgaaaatctcttgttttgaacgaagattttaaagaactcaactttccagcatcctcctctgttctaaccacttcagaaatatatgcagctgtgatacttgtagatttatatttagcaaaatgttagcatgtatgacaagacaatgagagtaattgcttgacaacaacctatgcaccaggtatttaacattaactttggaaacaaaaatgtacaattaagtaaagtcaacatatgcaaaatactgtacattgtgaacagaagtttaattcatagtaatttcactctctgcattgacttatgagataattaatgattaaactattaatgataaaaataatgcatttgtattgttcataatatcatgtgcacttcaagaaaatggaatgctactcttttgtggtttac5 200799_atggccgacaagaagaaggtgctggacaagtgtcaagaggtcatctcgtggctggacgccaacaccttggccgagaaggacgagtttgagcacaagaggaaggagctggagcaggtgtgtaaccccatcatcagcggactgtaccagggtgccggtggtcccgggcctgggggcttcggggctcagggtcccaagggagggtctgggtcaggccccaccattgaggaggtagattaggggcctttccaagattgctgtttttgttttggagcttcaagactttgcatttcctagtatttctgtttgtcagttctcaatttcctgtgtttgcaatgttgaaattttttggtgaagtactgaacttgctttttttccggtttctacatgcagagatgaatttatactgccatcttacgactatttcttctttttaatacacttaactcaggccatttttt 6 200845_s_attcctgtcacccattttgaagagtggcagaacttgaagttcaacttcctctgtaaatatccaagtataaagcccaggaacttctagaataacccagatgcgctttaattttttttaatatgttttgatcacagaacttctagaataacccagatgctctttcatattcttttaatacatcttgatcacagctgggggaaaaaaagctttttaattctgtaccttcctagtagataagtgaagagcagggaaagagacctttaaatattttgctataaaaaaatttgtgataagtttctatcaaaatggggagattgcagaaaaggcttcccttggctcccaaggaggtgtagcaggtgtgagcaatattagtgccatgtgcctttcacacagggtttgcatttatcagtctgttttccgatgatgtgtacatgaaagagtacaccatgtgaagagaagagagaatgattgaaaatgttttagtatagaactcttcttgcagtgggttgctattttctagatttta7 200859_x_atgtttgtagactctctgaccaaggccacctgtgccccccagcatggggccccgggtcctgggcctgctgacgccagcaaggtggtggccaagggcctggggctgagcaaggcctacgtaggccagaagagcagcttcacagtagactgcagcaaagcaggcaacaacatgctgctggtgggggttcatggcccaaggaccccctgcgaggagatcctggtgaagcacgtgggcagccggctctacagcgtgtcctacctgctcaaggacaagggggagtacacactggtggtcaaatgggggcacgagcacatcccaggcagcccctaccgcgttgtggtgccctgagtctggggcccgtgccagccggcagcccccaagcctgccccgctacccaagcagccccgccctcttcccctcaaccccggcccaggccgccctggccgcccgcctgtcactgcagctgcccctgccctgtgccgtgctgcgctcacctgcctccccagccagccgctgacctctcggctttcacttgggcagagggagccatttggtggcgctgct 8 200884_atcctcacccagattgaaactctcttcaagtctaaggactatgagttcatgtggaaccctcacctgggctacatcctcacctgcccatccaacctgggcaccgggctgcgggcaggtgtcgatatcaagctgcccaacctgggcaagcatgagaagttctcggaggtgcttaagcggctgcgacttcagaagcgaggcacaggcggtgtggacacggctgcggtgggcggggtcttcgacgtctccaacgctgaccgcctgggcttctcagaggtggagctggtgcagatggtggtggacggagtgaagctgctcatcgagatggaacagcggctggagcagggccaggccatcgacgacctcatgcctgcccagaaatgaagcccggcccacacccgacaccagccctgctgcttcctaacttattgcctgcagtgcccaccatgcacccctcgatgttgccgtctggcgagcccttagccttgctgtaaggaaggcttccgtcacccttggtagagtttat9 200897_s_atctctcttagctcagttactcaattcatacgtagtattttttaaaataattttatatctgtgtaccaccccatatatttcatattactgtttcacatgtacagctttctacttctttgtaagaacaccaaccaaccaaggtttaagtgattaataggcttgagcaccgggtggcagatgttctatgcagtgtggttcaagtttctttgaccgcacttatatgcattgctaatatggaatttaagataccatacacagtctctcatggacctatctctattgtagaattatgacttatgtcttacttggcaaatttttctgaatgtgacctttttttgctgatttgctgggtttgggattaactagcattattttgccacctt 10 200974_ataagagttacgagttgcctgatgggcaagtgatcaccatcggaaatgaacgtttccgctgcccagagaccctgttccagccatccttcatcgggatggagtctgctggcatccatgaaaccacctacaacagcatcatgaagtgtgatattgacatcaggaaggacctctatgctaacaatgtcctatcagggggcaccactatgtaccctggcattgccgaccgaatgcagaaggagatcacggccctagcacccagcaccatgaagatcaagatcattgcccctccggagcgcaaatactctgtctggatcggtggctccatcctggcctctctgtccaccttccagcagatgtggatcagcaaacaggaatacgatgaagccgggccttccattgtccaccgcaaatgcttctaaaacactttcctgctcctctctgtctctagcacacaactgtgaatgtcctgtggaattatgccttcagttcttttccaaatcattcctagccaaagctctgactcgt11 200986_atgacgaccagccaggatatgctctcaatcatggagaaattggaattcttcgatttttcttatgaccttaacctgtgtgggctgacagaggacccagatcttcaggtttctgcgatgcagcaccagacagtgctggaactgacagagactggggtggaggcggctgcagcctccgccatctctgtggcccgcaccctgctggtctttgaagtgcagcagcccttcctcttcgtgctctgggaccagcagcacaagttccctgtcttcatggggcgagtatatgaccccagggcctgagacctgcaggatcaggttagggcgagcgctacctctccagcctcagctctcagttgcagccctgctgctgcctgcctggacttgcccctgccacctcctgcctcaggtgtccgctatccaccaaaagggctcctgagggtctgggcaagggacctgcttctattagcccttctccatggccctgccatgctctccaaaccactttttgcagctttctc12 201041_s_atgcaataactctgggaggggctcgagagggctggtccttatttatttaacttcacccgagttcctctgggtttctaagcagttatggtgatgacttagcgtcaagacatttgctgaactcagcacattcgggaccaatatatagtgggtacatcaagtccatctgacaaaatggggcagaagagaaaggactcagtgtgtgatccggtttctttttgctcgcccctgttttttgtagaatctcttcatgcttgacatacctaccagtattattcccgacgacacatatacatatgagaatataccttatttatttttgtgtaggtgtctgccttcacaaatgtcattgtctactcctagaa 13 201058_s_atgcatcctcaaacatggcgccaaggataaacacgactaggccatccccagccccctgacacccagcccccgccagtcacccctccccgcacacacccgtccataccagctccctgcccatgaccctcgctcagggatccccctttgagggttagggtcccagttcccagtggaagaaacaggccaggagagtgcgtgccgagctgaggcagatgttcccacagtgaccccagagccctgggctatagtctctgacccctccaaggaaagaccaccttctggggacatgggctggagggcaggacctagaggcaccaagggaaccgcattccggggctgttccccgaggaggaagggaagcctctgtgtgccccccaggaggaagaggccctgagtcctgggatcagacaccccttcacgtgtatcccacacaaatgcaagctcaccaaggtccc 14 201061_s_attatagctctctttagctcaaccactctgtccatccagccaatggatgtccttccctgtacccaattcaagcttattttagggaagccttgaaactaccatgtatctggctctagctgagttattgaggattgagccagtgcaacgttaaactcagtgcacttacatttgatttaaatgatggttttatctgttgtgtgaagtggttcacccttgaggaccaggagcctccatatcctgactgaaaaccttttctgagacttagagtaacagtacttttggttccttgagttctcctgtctccagatacctaaatgaccttgacttttctgccttgtgaattcgtagtccaatcagctgaaattaaatcacttgggagggacgcatagaaggagctctaggaacacagtgccagtgcagaagtttctccaggtggcc15 201069_atctcagagccacccctaaagagatcctttgatattttcaacgcagccctgctttgggctgccctggtgctgccacacttcaggctcttctcctttcacaaccttctgtggctcacagaacccttggagccaatggagactgtctcaagagggcactggtggcccgacagcctggcacagggcagtgggacagggcatggccaggtggccactccagacccctggcttttcactgctggctgccttagaacctttcttacattagcagtttgctttgtatgcactttgtttttttctttgggtcttgttttttttttccacttagaaattgcatttcctgacagaaggactcaggttgtctgaagtcactgcacagtgcatctcagcccacatagtgatggttcccctgttcactctacttagcatgtccctaccgagtctcttctccactggatggaggaaaaccaagccgtggcttcccgctcagccctccctgcccctcccttcaaccattccccatgggaaat16 201105_atctcctggactcaatcatggcttgtggtctggtcgccagcaacctgaatctcaaacctggagagtgccttcgagtgcgaggcgaggtggctcctgacgctaagagcttcgtgctgaacctgggcaaagacagcaacaacctgtgcctgcacttcaaccctcgcttcaacgcccacggcgacgccaacaccatcgtgtgcaacagcaaggacggcggggcctgggggaccgagcagcgggaggctgtctttcccttccagcctggaagtgttgcagaggtgtgcatcaccttcgaccaggccaacctgaccgtcaagctgccagatggatacgaattcaagttccccaaccgcctcaacctggaggccatcaactacatggcagctgacggtgacttcaa17 201137_s_atggcagcattcaagtccgatggttcctgaatggacaggaggaaacagctggggtcgtgtccaccaacctgatccgtaatggagactggaccatccagatcctggtgatgctggaaatgaccccccagcagggagacgtctacatctgccaagtggagcacaccagcctggatagttccgtcaccgtggagtggaaggcacagtctgattctgcccagagtaagacattgacgggagctgggggcttcgtgctggggctcatcatctgtggagtgggactcttcatgcacaggaggagcaagaaagttcaacgaggatctgcataaacagggttcctgacctcaccgaaaagactaatgtgccttagaacaagcatttgctgtgttttgttaacacctggttccaggacagaccctcagcttcccaagaggatactgctgccaagaagttgctctgaagtcagtttctatcgttctgctctttgattcaaa18 201141_atagaggcgggatactttcagctttccatgtaactgtatgcataaagccaatgtagtccagtttctaagatcatgttccaagctaactgaatcccacttcaatacacactcatgaactcctgatggaacaataacaggcccaagcctgtggtatgatgtgcacacttgctagactcagaaaaaatactactctcataaatgggtgggagtattttggtgacaacctactttgcttggctgagtgaaggaatgatattcatatattcatttattccatggacatttagttagtgctttttatataccaggcatgatgctgagtgacactcttgtgtatatttccaaatttttgtatagtcgctgcacatatttgaaatcatatattaagactttccaaagatgaggtccctggtttttcatggcaacttgatcagtaaggatttcacctctgtttgtaacta 19 201150_s_atgactttttggaatagccctgtctagggcaaactgtggcccccaggagacactacccttccatgccccagacctctgtcttgcatgtgacaattgacaatctggactaccccaagatggcacccaagtgtttggcttctggctacctaaggttaacatgtcactagagtatttttatgagagacaaacattataaaaatctgatggcaaaagcaaaacaaaatggaaagtaggggaggtggatgtgacaacaacttccaaattggctctttggaggcgagaggaaggggagaacttggagaatagtttttgctttgggggtagaggcttcttagattctcccagcatccgcctttccctttagccagtctgctgtcctgaaacccagaagtgatggagagaaaccaacaagagatctcgaaccctgtctagaaggaatgtatttgttgctaaatttcgtagcactgtttacagttttcctccatgttatttatg 20201289_atgccacgattggagaatactttgcttcatagtattggagcacatgttactgcttcattttggagcttgtggagttgatgactttctgttttctgtttgtaaattatttgctaagcatattttctctaggcttttttccttttggggttctacagtcgtaaaagagataataagattagttggacagtttaaagcttttattcgtcctttgacaaaagtaaatgggagggcattccatcccttcctgaagggggacactccatgagtgtctgtgagaggcagctatctgcactctaaactgc21 201300_s_atttaggtcaagttcatagtttctgtaattggcttttgaatcaaagaatagggagacaatctaaaaaatatcttaggttggagatgacagaaatatgattgatttgaagtggaaaaagaaattctgttaatgttaattaaagtaaaattattccctgaattgtttgatattgtcacctagcagatatgtattacttttctgcaatgttattattggcttgcactttgtgagtatctatgtaaaaatatatatgtatataaaatatatattgcataggacagacttaggagttttgtttagagcagttaacatctgaagtgtctaatgcattaacttttgtaaggtactgaatacttaatatgtgggaaacccttttgcgtggtccttaggcttacaatgtgcactgaatcgtttcatgtaagaatccaaagtggacaccattaacaggtctttgaaatatgcatgtactttatattttctatatttgtaactttgcatgttcttgttttgtta 22201324_atcaccaaattacctaggctgaggttagagagattggccagcaaaaactgtgggaagatgaactttgtcattatgatttcattatcacatgattatagaaggctgtcttagtgcaaaaaacatacttacatttcagacatatccaaagggaatactcacattttgttaagaagttgaactatgactggagtaaaccatgtattcccttatcttttactttttttctgtgacatttatgtctcatgtaatttgcattactctggtggattgttctagtactgtattgggcttcttcgttaat23 201348_ataccagctctaggtccaattgttctgctctaactgatacctcaaccttggggccagcatctcccactgcctccaaatattagtaactatgactgacgtccccagaagtttctgggtctaccacactccccaaccccccactcctacttcctgaagggccctcccaaggctacatccccaccccacagttctccctgagagagatcaacctccctgagatcaaccaaggcagatgtgacagcaagggccacggaccccatggcaggggtggcgtcttcatga 24201426_s_attgtggatgtttccaagcctgacctcacggctgccctgcgtgacgtacgtcagcaatatgaaagtgtggctgccaagaacctgcaggaggcagaagaatggtacaaatccnagtttgctgacctctctgaggctgccaaccggnacnatgacgccctgcgccaggcnaagcaggagtccnctgagtaccggagacaggtgcagtccctcacctgtgaagtggatgcccttaaaggaaccaatgagtccctggaacgccagatgcgtgaaatggaagagaactttgccgttgaagctgctaactaccaagacactattggccgcctgcaggatgagattcagaatatgaaggaggaaatggctcgtcaccttcgtgaataccaagacctgctcaatgttaagatggcccttgacattgagattgccacct 25 201427_s_atgatccagaaatacttaacacgtgaatattttgctaaaaaagcatatataactattttaaatatccatttatcttttgtatatctaagactcatcctgatttttactatcacacatgaataaaggcctttgtatctttctttctctaatgttgtatcatactcttctaaaacttgagtggctgtcttaaaagatataaggggaaagataatattgtctgtctctatattgcttagtaagtatttccatagtcaatgatggtttaataggtaaaccaaaccctataaacctgacctcctttatggttaatactattaagcaagaatgcagtacagaattggatacagtacggatttgtccaaat 26 201438_atctccagcagttctctcgaatactttgaatgttgtgtaacagttagccactgctggtgtttatgtgaacattcctatcaatccaaattccctctggagtttcatgttatgcctgttgcaggcaaatgtaaagtctagaaaataatgcaaatgtcacggctactctatatacttttgcttggttcattttttttcccttttagttaagcatgactttagatgggaagcctgtgtatcgtggagaaacaagagaccaactttttcattccctgcccccaatttcccagactagatttcaagctaattttctttttctgaagcctctaacaaatgatctagttcagaaggaagcaaaatcccttaatctatgtgcaccgttgggaccaatgccttaattaaagaatttaaaaaagttgtaatagagaatatttttggcattcctctcaatgttgtgtgtt 27 201495_x_atcaagtgcagcgatggggagcgggcccgggcggagctcaatgacaaagtccacaagctgcagaatgaagttgagagcgtcacagggatgcttaacgaggccgaggggaaggccattaagctggccaaggacgtggcgtccctcagttcccagctccaggacacccaggagctgcttcaagaagaaacccggcagaagctcaacgtgtctacgaagctgcgccagctggaggaggagcggaacagcctgcaagaccagctggacgaggagatggaggccaagcagaacctggagcgccacatctccactctcaacatccagctctccgactcgaagaagaagctgcaggactttgccagcaccgtggaagctctggaagaggggaagaagaggttccagaaggagatcgagaacctcacccag 28 201496_x_ttcaagtccaagttcaagtccaccatcgcggcgctggaggccaagattgcacagctggaggagcaggtcgagcaggaggccagagagaaacaggcggccaccaagtcgctgaagcagaaagacaagaagctgaaggaaatcttgctgcaggtggaggacgagcgcaagatggccgagcagtacaaggagcaggcagagaaaggcaatgccagggtcaagcagctcaagaggcagctggaggaggcagaggaggagtcccagcgcatcaacgccaaccgcaggaagctgcagcgggagnnggatgaggccacggagagcaacgaggccatgggccgcgaggtgaacgcactcaagagcaagctcagagggccccccccacaggaaacttcgcagtgatgcaccaggcgaggaaacgagacctctttcgttccttctagaaggtctggaggacgtagagttattgaaaatgcagatggttctgaggaggaaacggacactcgagacgcagacttcaatggaaccaaggccagtgaataagcaactttctacagttttgcaccacgg 29201497_x_attgagccaggaagaacgctccagcccaggacttcgaggctgcaatgagctataattgcatcattgcactccagcctgggcaacagagaccctgtctcaaccaccaccaccaccaccacccctactacccctgtattcaaggtaaaaattgaagtttgtatgatgtaagagatgagaaaaacccaacaggaaacacagacacatcctccagttctatcaatggattgtgcagacactgagtttttagaaaaacatatccacggtaaccggtccctggcaattctgtttacatgaaatggggagaaagtcaccgaaatgggtgccgccggcccccactcccaattcattccctaacctgcaaacctttccaacttctcacgtcaggcctttgagaattctttccccctctcctggtttccacacctcagacacgcacagttcaccaagtgccttctgtagtcacatgaattgaaaaggagacgctgctcccacggaggggagcaggaatgctgcactgtttacaccctgactgtgcttaaaa 30 201539_s_attgaagtgcaacaaggccatcacatctggaggaatcacttaccaggatcagccctggcatgccgattgctttgtgtgtgttacctgctctaagaagctggctgggcagcgtttcaccgctgtggaggaccagtattactgcgtggattgctacaagaactttgtggccaagaagtgtgctggatgcaagaaccccatcactgg31 201540_atcagggctgtcatcaacatggatatgacatttcacaacagtgactagttgaatcccttgtaacgtagtagttgtctgctctttgtccatgtgttaatgaggactgcaaagtcccttctgttgtgattcccaggacttttcctcaagaggaaatctggatttccacctaccgcttacctgaaatgcaggatcacctacttactgtattctacattattatatgacatagtataatgagacaatatcaaaagtaaacatgtaatgacaatacatactaacattcttgtaggagtggttagagaagctgatgcctcatttctacattctgtcattagctattatcatctaacgtttcagtg 32 201616_s_atcttgagaccaggagacgtatccagcaagcggaacctctgggaaaagcaatctgtggataaggtcacttcccccactaaggtttgagacagttccagaaagaacccaagctcaagacgcaggacgagctcagttgtagagggctaattcgctctgttttgtatttatgttgatttactaaattgggttcattatcttttatttttcaatatcccagtaaacccatgtatattatcactatatttaataatcacagtctagagatgttcatggtaaaagtactgcctttgcacaggagcctgtttctaaagaaacccatgctgtgaaatagagacttttctactgatcatcataactctgtatctgagcagtgataccaaccacatctgaagtcaacagaagatccaagtttaaaattgcctgcggaatgtgtgcagtatctagaaa 33 201617_x_attgttgtttctgcactttataataaagcatggaagaaattatcttagtaggcaattgtaacactttttgaaagtaacccatttcagatttgaaatactgcaataatggttgtctttaaaaaaaaaaagaatgtactgttaaggtattactttttttcatgctgatgattcatatctaaattacattattatgttagctgacagtggtactgattttttaggttggttgttttgtggatttctttagtagtgatagtagcctgaaccacattttagataactcaattatgtatgtatgtgcatacacatatacaaacacactaatggtagaatgcttttttatgtgctagactattatatttagtagtatgtcattgtaactagccaatatcacagcttttgaaaaattaaaaaatcatcatcactataatatttcatatttgccaacagaaacatggcagataggtatcaatatgttttcaatgcctgatgacctat 34 201645_atttttaccaaagcatcaatacaaccagcccaaccatcggtccacacctgggcatttggtgagaatcaaagctgaccatggatccctggggccaacggcaacagcatgggcctcacctcctctgtgatttctttctttgcaccaaagacatcagtctccaacatgtttctgttttgttgtttgattcagcaaaaatctcccagtgacaacatcgcaatagttttttacttctcttaggtggctctgggatgggagaggggtaggatgtacaggggtagtttgttttagaaccagccgtattttacatgaagctgtataattaattgtcattatttttgttagcaaagattaaatgtgtcattggaagccatccctttttttacatttcatacaacagaaaccagaaaagcaatactgtttccattttaaggatatgattaatattattaatataataatgatgatgatgatgatgaaaactaaggatttttcaagagatctttctttccaaaacatttctggacagtacctgattgt35 201667_atgagtggactattaaatgtgcctaaatgaattttgcagtaactggtattcttgggttttcctacttaatacacagtaattcagaacttgtattctattatgagtttagcagtcttttggagtgaccagcaactttgatgtttgcactaagattttatttggaatgcaagagaggttgaaagaggattcagtagtacacatacaactaatttatttgaactatatgttgaagacatctaccagtttctccaaatgccttttttaaaactcatcacagaagattggtgaaaatgctgagtatgacacttttcttcttgcatgcatgtcagctacataaacagttttgtacaatgaaaattactaatttgtttgacattccatgttaaactacggtcatgttcagcttcattgcatgtaatgtagacctagtccatcaga36 201739_attgctgtgtgaaccgtcgtgtgagtgtggtatgcctgatcacagatggattttgttataagcatcaatgtgacacttgcaggacactacaacgtgggacattgtttgtttcttccatatttggaagataaatttatgtgtagacttttttgtaagatacggttaataactaaaatttattgaaatggtcttgcaatgactcgtattcagatgcctaaagaaagcattgctgctacaaatatttctatttttagaaagggtttttatggaccaatgccccagttgtcagtcagagccgttggtgtttttcattgtttaaaatgtcacctgtaaaatgggcattatttatgtttttttttttgcattcctgataattgtatgtattgtataaagaacgtctgtacattgggttataacactagtatatttaaacttacaggcttatttgtaatgtaaaccaccattttaatgtactgtaattaacatggttataatacgtacaatccttccctcatcccatcacacaactttttttg37 201743_atccatccagaatctagcgctgcgcaacacaggaatggagacgcccacaggcgtgtgcgccgcactggcggcggcaggtgtgcagccccacagcctagacctcagccacaactcgctgcgcgccaccgtaaaccctagcgctccgagatgcatgtggtccagcgccctgaactccctcaatctgtcgttcgctgggctggaacaggtgcctaaaggactgccagccaagctcagagtgctcgatctcagctgcaacagactgaacagggcgccgcagcctgacgagctgcccgaggtggataacctgacactggacgggaatcccttcctggtccctggaactgccctcccccacgagggctcaatgaactccggcgtggtcccagcctgtgcacgttcgaccctgtcggtgggggtgtcgggaaccctggtgctgctccaaggggcccggggctttgcctaagatccaagacagaataatgaatggactcaaactgccttggcttcaggggagtcccgtcaggacgttgaggacttttcgaccaattcaacc 38 201744_s_atcaaatgatgtgcaaaaccttttactggttgcatggaaatcagccaagttttataatccttaaatcttaatgttcctcaaagcttggattaaatacatatggatgttactctcttgcaccaaattatcttgatacattcaaatttgtctggtaaaaaaataggtggtagatattgaggccaagaatattgcaaaatacatgaagcttcatgcacttaaagaagtatttttagaataagaatttgcatacttacctagtgaaacttttctagaattatttttcactctaagtcatgtatgtttctct39 201842_s_attcagcagtatagggaccttccgcacaagctctgtgttaagattgacaataatagtggggccattttcattttagtcttttctaagagtcaaccacaggcatttaagtcagccaaagaatattgttaccttaaagcactattttatttatagatatatctagtgcatctacatctctatactgtacactcacccataattcaaacaattacaccatggtataaagtgggcatttaatatgtaaagattcaaagtttgtctttattactatatgtaaattagacattaatccactaaactggtcttcttcaagagagctaagtatacactatctggtgaaacttggattctttcctataaaagtgggaccaagcaatgatgatcttctgtggtgcttaaggaaacttactagagctccactaacagtctcataaggaggcagccatcataaccattga 40 201852_x_atgtgccaatcctttgaatgttccacggaaacactggtggacagattctagtgctgagaagaaacacgtttggtttggagagtccatggatggtggttttcagtttagctacggcaatcctgaacttcctgaagatgtccttgatgtgcagctggcattccttcgacttctctccagccgagcttcccagaacatcacatatcactgcaaaaatagcattgcatacatggatcaggccagtggaaatgtaaagaaggccctgaagctgatggggtcaaatgaaggtgaattcaaggctgaaggaaatagcaaattcacctacacagttctggaggatggttgcacgaaacacactggggaatggagcaaaacagtctttgaatatcgaacacgcaaggctgtgagactacctattgtagatattgcaccctatgacattggtggtcctgatcaagaatttggtgtggacgttggccct 41 201858_s_atcctggttctggaatcctcagttcaaggttatcctacgcagagagccaggtaccaatgggtgcgctgcaatccagacagtaattctgcaaactgccttgaagaaaaaggaccaatgttcgaactacttccaggtgaatccaacaagatcccccgtctgaggactgacctttttccaaagacgagaatccaggacttgaatcgtatcttcccactttctgaggactactctggatcaggcttcggctccggctccggctctggatcaggatctgggagtggcttcctaacggaaatggaacaggattaccaactagtagacgaaagtgatgctttccatgacaaccttaggtctcttgacaggaatctgccctcagac 42 201859_attatgctttaatgctgttatctatcttattgttcttgaaaatacctgcattttttggtatcatgttcaaccaacatcattatgaaattaattagattcccatggccataaaatggctttaaagaatatatatatatttttaaagtagcttgagaagcaaattggcaggtaatatttcatacctaaattaagactctgacttggattgtgaattataatgatatgccccttttcttataaaaacaaaaaaaaaataatgaaacacagtgaatttgtagagtgggggtatttgacatattttacagggtggagtgtactatatactattacctttgaatgtgtttgcagagctagtggatgtgtttgtctacaagtatgattgctgttacataacaccccaaattaactcccaaattaaaacacagttgtgctgtcaatacctcatactgctttacctttttttcctggatatctgtgtattttc 43 201865_x_atgttgagtcgtcatcacttttcagtgatgggagagtagatggtgaaatttattagttaatatatcccagaaattagaaaccttaatatgtggacgtaatctccacagtcaaagaaggatggcacctaaaccaccagtgcccaaagtctgtgtgatgaactttctcttcatactttttttcacagttggctggatgaaattttctagactttctgttggtgtatcccccccctgtatagttaggatagcatttttgatttatgcatggaaacctgaaaaaaagtttacaagtgtatatcagaaaagggaagttgtgccttttatagctattactgtctggttttaacaatttcctttatatttagtgaactacgcttgctcattttttcttacataattttttattcaagttattgtacagctgtttaagatgggcagctagttcgtagctttcccaaataaactctaaacattaatcaatcatctgtgtgaaaatgggttggtgcttctaacctgatggcacttagctatcagaagaccacaaaaattgactcaaatctccagtattcttg 44 201893_x_attctcctacatccgcattgctgataccaatatcaccagcattcctcaaggtcttcctccttcccttacggaattacatcttgatggcaacaaaatcagcagagttgatgcagctagcctgaaaggactgaataatttggctaagttgggattgagtttcaacagcatctctgctgttgacaatggctctctggccaacacgcctcatctgagggagcttcacttggacaacaacaagcttaccagagtacctggtgggctggcagagcataagtacatccaggttgtctaccttcataacaacaatatctctgtagttggatcaagtgacttctgcccacctggacacaacaccaaaaaggcttcttattcgggtgtgagtcttttcagcaacccggtccagtactgggagatacagccatccaccttcagatgtgtctacgtgcgctctgccattcaactcggaaactataagtaattctcaagaaagccctcatttttataacctgg45 201920_atgtatcaggcttcaattccattatgttttaatgttgtctctgaagatgacttgtgatttttttttcttttttttaaaccatgaagagccgtttgacagagcatgctctgcgttgttggtttcaccagcttctgccctcacatgcacagggatttaacaacaaaaatataactacaacttcccttgtagtctcttatataagtagagtccttggtactctgccctcctgtcagtagtggcaggatctattggcatattcgggagcttcttagagggatgaggttctttgaacacagtgaaaatttaaattagtaacttttttgcaagcagtttattgactgttattgctaagaagaagtaagaaagaaaaagcctgttggcaatcttggttatttctttaagatttctggcagtgtgggatggatgaatgaagtggaatgtgaactttgggcaagttaaatgggacagccttccatgttcatttgtctacctcttaactga 46 201957_atgttgtgcctaccactggctggcacaccagggcaatgatttccctgcagaaggaaggaaagaatgtttcacccttgcatccttcttggagaagctacagcctgtgctcagttgagtggttcacactcagactttggctttatggttttccttcctccttgtctttgccctgaccttgatcaacaggggtgaaaagaaccaccctgaggtttccatgcctctcccattttagtggtagcattttgtgtctttactccacccttcaccctagttccaccaaggttcacacaccagatgtaactgtttttcagctgagttgtatggattaacttcagtccactgtaaatacacctgggatggggtggggttggggttgtttagggagaagcagccagacttgctttgtgaactgaatgtatttttatgcaattttgagtggcctttcaaccctaaga 47 202007_attatcagtagctcgtgttatctttttatcaactgcttcccagngtcctaaaacaatagaaattttggattgaaaagttcagcataaggagtttgagtcagtaaaggatgggataaaggagtcgagatgattcaatgaaaagtatcacaaaaaagagattgatcaacaagagaaataaaaaagcccaagaggaagtggtaggggaaggaatttaagaacagcaataagtaaaactcttaagtaactccaaaaagaaaatggtacattttgccaaagaccacttatacttgagaacatggaagaatttgcctgatactctctttggggaaaagagtctctcctcttttcctcaaaccccagtacactcagcctctctgccccaccttctcctgactttgtcctcacttgcttctgcagtacattggaacctgaattgaaagaaagtcttccttgaataattggagtttgtcttgagaggcaaatatagccccaagaatcacaagattcgaggaccatgtaggtcttttacgtagcccaaatccataaattagtctcactttttgtatttatcgtttcatattaaaccctctatatca 48202037_s_attaacacttggctcttggtacctgtgggttagcatcaagttctccccagggtagaattcaatcagagctccagtttgcatttggatgtgtaaattacagtaatcccatttcccaaacctaaaatctgtttttctcatcagactctgagtaactggttgctgtgtcataacttcatagatgcaggaggctcaggtgatctgtttgaggagagcaccctaggcagcctgcagggaataacatactggccgttctgacctgttgccagcagatacacaggacatggatgaaattcccgtttcctctagtttcttcctgtagtactcctcttttagatcc 49 202069_s_atcagtcactctaaatggacaccacatgaacctctgtttagaatacctacgtatgtatgcattggtttgcttgtttcttgacagtacatttttagatctggccttttcttaacaaaatctgtgcaaaagatgcaggtggatgtccctaggtctgttttcaaagaactttttccaagtgcttgttttatttattaagtgtctacctggtaaatgttttttttgtaaactctgagtggactgtatcatttgctattctaaaccattttacacttaagttaaaatagtttctcttcagctgtaaataacaggatacagaattaacaagagaaaatgtctaactttttaagaaaaaccttattttcttcggtttttgaaaaacataatggaaataaaacaggatattgacataatagcacaaaatgacactcttctaaaactaaatgggcacaagagaattttcctggga 50 202133_atgtcaaaacctaattgcaattctgttaaatctaagtaatttttagacagtgtttcaccgtattatttaggatgtgaaatgccatttctttcactgattacaccatatacaggaaacaggtaaaacagtgaaaactttattgtgctggttgatgccaacttggttgaaaagctctctgcagaagaagtgatctagactgacagaagtgttgctaattacaagttgtgttctcatgacgtaattagaaagtaacttctcaaagtacaacttttatgaaaaaaataagctgttaaaaaaaggaaatcgtaggttaatttaattgggaaaatgggcaattgacagagaccattttcctaacacatatatgtgctagtactttaactttttaaaattttacttctacgttttgtaatataaaaatttctattttaagtttagaatgttatacgtaccgaaagtatgcagccaaatcgatcagatcaaaccattttacctggagtt 51 202222_s_atagctgtgagccttggctgttggcagtgagtgagcctggctcttgtgctggatggagcccaggcgggagcggtggccctgtccctcccacctctgtgacctgaggcctacgctttggctctggagatagccccagagcagggtgttgggatactgcagggccaggactgagcccc 52202242_atctgttagctcctcactgtggtaaatgccacacacctttaagtagataagcagacgatagttatctgttcttttgacttaatctcatttggtttgattttccctctactaaggctttcctaccttcttcaggctgcctaagacatgtaagcgaaacacttcaataattgtccatgaggagaaaaaaagcattgtcatgcatgaaggaaactgaacttgaggtggcctccttgcttgttacatacctgggtatgtgtaggcagtttagtgcatctttgcctctcagttgaaacctgtataaccctgttacaaagctgtgttgttgcttcttgtgaaggccatgatattttgttttttccccaattaattgctattgtgttattttactaacttctctctgtattttttcttgcattgacattatagacattgaggacctcatccaaacaatttaaaaatgagtgtgaagggggaacaagtcaaaatatttttaaaagatcttcaaaaataatgcctctgtctagcatgccaac53 202266_attgtcagagttttcaacggtgcttatagctgccagctggattccaaacaggtaccccattgtctctgagctaatgtttatatttttccattcaggcaccgaaatagttaatatttaaaataagtcttcaaaagaaaacataagagattattgagttcttgggactggatcctttatttcataagttcagatcatcttaaatgaaaatgccatgattatctgcagttaagtagatgacagctattctacatcagacttgatttttgtcagctaattacataattggtaagctataattgaaaccttatggcttaaaattccttaactcctttttgattcatgtttgtagtcatgttgtcaacagaggcaaagttaagcttgatgatggttaaaatcggtttgatagcaccatgggacatttttctaacaaaaataaatgcatgaagagacatagccttttagttttgct 54 202274_ataagagctatgagctgccagatgggcaggttatcaccattggcaatgagcgcttccgctgccctgagaccctcttccagccttcctttattggcatggagtccgctggaattcatgagacaacctacaattccatcatgaagtgtgacattgacatccgtaaggacttatatgccaacaatgtcctctctgggggcaccaccatgtaccctggcattgctgacaggatgcagaaggagatcacagccctggcccccagcaccatgaagatcaagattattgctcccccagagcggaagtactcagtctggatcgggggctctatcctggcctctctctccaccttccagcagatgtggatcagcaagcctgagtatgatgaggcagggccctccattgtccacaggaagtgcttctaaagtcagaacaggttctccaaggatcccc 55 202283_atcaactgcccttgaccggaagcatgagtatcatcttcttcctgcccctgaaagtgacccagaatttgaccttgatagaggagagcctcacctccgagttcattcatgacatagaccgagaactgaagaccgtgcaggcggtcctcactgtccccaagctgaagctgagttacgaaggcgaagtcaccaagtccctgcaggagatgaagctgcaatccttgtttgattcaccagactttagcaagatcacaggcaaacccatcaagctgactcaggtggaacaccgggctggctttgagtggaacgaggatggggcgggaaccacccccagcccagggctgcagcctgcccacctcaccttcccgctggactatcaccttaaccagcctttcatcttcgtactgagggacacagacacaggggcccttctcttcattggcaagattctggaccccaggggcccctaatatcccagtttaatattccaataccctagaagaaaacccgagggacagcagattccacag 56 202291_s_atctgacctgcaggacgaaaccatgaagagcctgatccttcttgccatcctggccgccttagcggtagtaactttgtgttatgaatcacatgaaagcatggaatcttatgaacttaatcccttcattaacaggagaaatgcaaataccttcatatcccctcagcagagatggagagctaaagtccaagagaggatccgagaacgctctaagcctgtccacgagctcaatagggaagcctgtgatgactacagactttgcgaacgctacgccatggtttatggatacaatgctgcctataatcgctacttcaggaagcgccgaggggccaaatgagactgagggaagaaaaaaaatctctttttttctggaggctggcacctgattttgtatccccctgtagcagcattactgaaatacataggcttatatacaatgcttctttcct 57 202350_s_atgaagccctggaaaatcgcctgagatacagatgaagattagaaatcgcgacacatttgtagtcattgtatcacggattacaatgaacgcagtgcagagccccaaagctcaggctattgttaaatcaataatgttgtgaagtaaaacaatcagtactgagaaacctggtttgccacagaacaaagacaagaagtatacactaacttgtataaatttatctaggaaaaaaatccttcagaattctaagatgaatttaccaggtgagaatgaataagctatgcaaggtattttgtaatatactgtggacacaacttgcttctgcctcatcctgccttagtgtgcaatctcatttgactatacgataaagtttgcacagtcttacttctgtagaacactggccataggaaatgctgtttttttgtactggactttaccttgatatatgt 58 202388_atgctggtatcagaacagcttccctcactgtgtacagaacgcaagaagggaataggtggtctgaacgtggtgtctcactctgaaaagcaggaatgtaagatgatgaaagagacaatgtaatactgttggtccaaaagcatttaaaatcaatagatctgggattatgtggccttaggtagctggttgtacatctttccctaaatcgatccatgttaccacatagtagttttagtttaggattcagtaacagtgaagtgtttactatgtgcaagggtattgaagttcttatgaccacagatcatcagtactgttgtctcatgtaatgctaaaactgaaatggtccgtgtttgcattgttaaaaatgatgtgtgaaatagaatgagtgctatggtgttgaaaactgcagtgtccgttatgagtgccaaaaatctgtcttgaaggcagctacactt 59 202403_s_ataacctgaaaacatcccagccaagaactggtataggagctccaaggacaagaaacacgtctggctaggagaaactatcaatgctggcagccagtttgaatataatgtagaaggagtgacttccaaggaaatggctacccaacttgccttcatgcgcctgctggccaactatgcctctcagaacatcacctaccactgcaagaacagcattgcatacatggatgaggagactggcaacctgaaaaaggctgtcattctacagggctctaatgatgttgaacttgttgctgagggcaacagcaggttcacttacactgttcttgtagatggctgctctaaaaagacaaatgaatggggaaagacaatcattgaatacaaaacaaataagccatcacgcctgcccttccttgatattgcacctttggacatcggtggtgctgaccaggaattctttgtggacattggcccagtctgtt 60 202555_s_atgagccattggaagactgtcctctatggcaatgatctcagggctcagtggcaggaaatcctcaacagggtcaccaaccagcccgctcaatgcagaaaaactagaatctgaagatgtgtcccaagctttccttgaggctgttgctgaggaaaagcctcatgtaaaaccctatttctctaagaccattcgcgatttagaagttgtggagggaagtgctgctagatttgactgcaagattgaaggatacccagaccccgaggttgtctggttcaaagatgaccagtcaatcagggagtcccgccacttccagatagactacgatgaggacgggaactgctctttaattattagtgatgtttgcggggatgacgatgccaagtacacctgcaaggctgtcaacagtcttggagaagccacctgcac61 202620_s_atttatcaagtgtcaagatcagcaagtgtccttaagtcaaataggtttttttttgttggtggttgtgcttgctttccttttttagaaagttctagaaaataggaaaacgaaaaatttcattgagatgagtagtgcatttaattattttttaaaaaactttttaagtacttgaattttatatcaggaaaacaaagttgttgagccttgcttcttccgttttgccctttgtctcgctccttattcttttttggggggagggttatttgcttttttatcttcctggcataatttccattttattcttctgagtgtctatgttaacttccctctatcccgcttataaaaaaattctccaacaaaaatacttgttgacttgatgttttatcacttctctaagtaaggttgaaatatccttattgtagctactgtttttaatgtaaaggttaaacttgaaaagaaattcttaatcacggtgccaaaattcattttctaacaccatgtgtt 62 202686_s_atagattctaacggtctgttctgtttcaaggcactctagattccattggtccaagattccggatcctaagcatctaagttataagactctcacactcagttgtgactaactagacaccaaagttctaataatttctaatgttggacacctttaggttctttgctnnattctgcctctctaggaccatggttaagagtccaagaatccacatttctaaaatcttatagttctaggcactgtagttctaagactcaaatgttctaagtttctaagattctaaaggtccacaggtctagactattaggtgcaatttcaaggttctaaccctatactgtagtattctttggggtgcccctctccttcttagctatcattgcttcctcctccccaactgtgggggtgtgcccccttcaagcctgtgcaatgcattagggatgcctcctttccgcaggggatggacgatctcccacctttcgggccatgttgcccccgtgagccaatccctcaccttctgagtacagagtgtggactctggtgcctcca63 202731_atggctctggaggtgggcagcaatctgtcaatcaccttgttaaagagattgatatgctgctgaaagaatatttactctctggagacatatctgaagctgaacattgccttaaggaactggaagtacctcattttcaccatgagcttgtatatgaagctattataatggttttagagtcaactggagaaagtacatttaagatgattttggatttattaaagtccctttggaagtcttctaccattactgtagaccaaatgaaaagaggttatgagagaatttacaatgaaattccggacattaatctggatgtcccacattcatactctgtgctggagcggtttgtagaagaatgttttcaggctggaataatttggaaacaactcagagatctttgtccttcaaggggcagaaagcgttttgtaagcgaaggagatggaggtcgtcttaaaccagagagctactgaatataagaactcttgcagtcttagatgttat 64202741_atgtaagattcctcctaactttcacagtcgatgacaagattgtctttttatctgatattttgaagggtatattgctttgaagtaagtctcaataaggcaatatattttagggcatctttcttcttatctctgacagtgttcttaaaattatttgaatatcataagagccttggtgtctgtcctaattcctttctcactcaccgatgctgaatacccagttgaatcaaactgtcaacctaccaaaaacgatattgtggcttatgggtattgctgtctcattcttggtatattcttgtgttaactgcccattggcctgaaaatactcattgtaagcctgaaaaaaaaaatctttcccactgttttttctgcttgttgtaagaatcaaatgaaataatgtatgtgaaagcaccttgtaaactgtaacctatcaatgtaaaatgttaaggtgtgttgttatttcattaattacttctttgtttagaatggaatttcctatgcactactgtagc 65 202742_s_attacacttttttttgccaactgacttaacaacattgctgtcaggtggaaatttcaagcacttttgcacatttagttcagtgtttgttgagaatccatggcttaacccacttgttttgctatttttttctttgcttttaattttccccatctgattttatctctgcgtttcagtgacctaccttaaaacaacacacgagaagagttaaactgggttcattttaatgatcaatttacctgcatataaaatttatttttaatcaagctgatcttaatgtatataatcattctatttgctttattatcggtgcaggtaggtcattaacaccacttcttttcatctgtaccacaccctggtgaaacctttgaagacataaaaaaaacctgtctgagatgttctttctaccaatctatatgtctttcggttatcaagtgtttctgcatggtaatgtc66 202746_ataaactactaaccactgcaagctcttgtcaaattttagtttaattggcattgcttgttttttgaaactgaaattacntgagtttcattttttctttgaatttatagggtttagatttctgaaagcagcatgaatatatcacctaacatcctgacaataaattccatccgttgttttttttgtttgtttgttttttcttttcctttaagtaagctctttattcatcttatggtgcagcaattttaaaatttgaaatattttaaattgtttttgaactttttgtgtaaaatatatcagatctcaacattgttggtttcttttgtttttcattttgtacaactttcttgaatttagaaattacatctttgcagttctgttaggtgctctgtaattaacctgacttatatgtgaacaattttcatgagacagtcatttttaactaatgcagtgattctttctcactactatctgtattgtggaatgcacaaaattgtgtaggtgctgaatgctgtaaggagtttaggttgtatgaattctacaaccctataata67 202760_s_atgagatactatttttgctgagcaaccagtgtgtttcaggatgatacaaagaaaaatatagaatagaaataagtgcaggcttggaatcagctacaaatcctaaagatggggtgtgtgtggatgtgtgtgtgtgtgtgtgtacaccattgtgtgtttgtaaaatgtgtatgttcatgagtaagggtgtgtgtgtgtgtgtattaaaattccagagtgaccgtggcacttgggtgtacaggtaattcctccagagctgtttgctggcttcaggagtggagtgagaatttcttttttatgaaaagggatataaaggcaccgagctgatgcagtatttgtaatattaagttgacctaacaaggtatttgcatgagtcacaattacaaagttttgagcggttttgtaatttgacatttaggaaagtctcctatttattctcatactttacattcatgcttagtatactatagaggatgccagctttaatctttctg 68 202766_s_atgctttcaattgatggactactctattttttgcaaatttgtaaactttgcttctccaaatacaagtactaggttgtccatttatggtacctatttggtgctagtaaattttcaaactagatttataaatgcactgtaatatgtacacaacttagaaaccaaattacaagtattcagttccaatacttcattaatttcaatcaaccaaagttagttcagtagcttatctcagttatgagtataatacattacatgtaaattaagtgtgtgtatactgtaatcgtgctattttttatcattgaaacatttataaactagaataataatgcccttaatgtgagggtttgtaatggtgcttattaagaccaaagacttgttaaatgtatacaccaagtggtaatgaaatttcgtgactggcccacacgtgcatagaggtctgggaggaccaggaaacagcctcagtggccagaggatcaccagtgcatccttcatcacagcatgtgcaatatgccaagattaccctcggtcattcctgtcaacaaggg69 202768_atgcgtgagtgtgtgagcgcttctgcagcctcggcctaggtcacgttggccctcaaagcgagccgttgaattggaaactgcttctagaaactctggctcagcctgtctcgggctgacccttttctgatcgtctcggcccctctgattgttcccgatggtctctctccctctgtcttttctcctccgcctgtgtccatctgaccgttttcacttgtctcctttctgactgtccctgccaatgctccagctgtcgtctgactctgggttcgttggggacatgagattttattttttgtgagtgagactgagggatcgtagatttttacaatctgtatctttgacaattctgggtgcgagtgtgagagtgtgagcagggcttgctcctgccaaccacaattcaatgaatccccgacccccctaccccatgctgtacttgtggttctctttttgtattttgcatctgaccccggggggctgggacagattggcaatgggccgtccc 70 202838_atagaaagaggcgctgctcactgttttcctgcttcagtttttctcttatagtaccatcactataatcaacgaacttctcttctccacccagagatggcttttccaacacattttaattaaaggaactgagtacattaccctgatgtctaaatggaccaaagatctgagatccattgtgattatatctgtatcaggtcagcagaagaaggaactgagcagttgaactctgagttcatcaattctaatatttggaaattatctacaatggaatcttccctctgttctctgataacctacttgcttactcaatgcctttaagccaagtcaccctgttgcctatgggaggaggtggaaggatttggcaagctcaaccacatgctatttagttagcatcagttgtcaccaacagtctttctgcaaagggcaggagagctttgggggaaaggaaaaggcttaccaggctgctatggtcaactcttcagaa 71 202888_s_atagccctggagaagacgaaagccaacatcaagtgggtgaaggagaacaaggaggtggtgctccagtggttcacagaaaacagcaaatagtccccagcccttgaagtcacccggccccgatgcaaggtgcccacatgtgtccatcccagcggctggtgcagggcctccattcctggagcccgaggcaccagtgtcctcccctcaaggacaaagtctccagcccacgttctctctgcctgtgagccagtctagttcctgatgacccaggctgcctgagcacctcccagcccctgcccctcatgccaaccccgccctaggcctggcatggcacctgtcgcccagtgccctggggctgatctcagggaagcccagctccagggccagatgagcagaagctctcgatggacaatgaacggccttgctgggggccgccctgtaccctctttcacctttccctaaagaccctaaatctgaggaatcaacagggcagcagatctgtatatttttttc72 202920_atattatctggtcttttcctgttgtgcaaaaatgactcattgctccgaatgtcaaaaacaaatgcgacaaacaatggcacttcatcatttaaagtaatgttgccaagagaaaaaatttcctgggagggaggtttcccacaagccaaatctcctaagcctcaaatgctagcactttttggcagttggataggaaatgagacattctttggcagccaaaataagagaggccgatggtgaaactttttgagacaccctatggccttcttgtcaaaaccttcactggagctcaagaaaagcatttctgttgtgttatttgcagtgcagatgatgtctgtgtaacaacataatggttattcacctttttttgattttgatttttgctgtgttatcaaaaacttgaatactgtgagaagaagtgaattttcagttgacgaatcagcatcttgttcccatggtgataac 73 202953_atcttcgaccacgtgatcaccaacatgaacaacaattatgagccccgcagtggcaagttcacctgcaaggtgcccggtctctactacttcacctaccacgccagctctcgagggaacctgtgcgtgaacctcatgcgtggccgggagcgtgcacagaaggtggtcaccttctgtgactatgcctacaacaccttccaggtcaccaccggtggcatggtcctcaagctggagcagggggagaacgtcttcctgcaggccaccgacaagaactcactactgggcatggagggtgccaacagcatcttttccgggttcctgctctttccagatatggaggcctgacctgtgggctgcttcacatccaccccggctccccctgccagcaacgctcactctacccccaacaccaccccttgcccagccaatggacacagtagggcttggtgaatgctgctgagtgaatgagtaaataaactcttcaaggccaaggaacagtggtctaattcaactctgtgtcccagcactggcacaccagaagtgccatgctcagaaa 74 202957_attgatgagctttcctttgatccggacgacgtaatcactgacattgagatggtggacgagggctggtggcggggacgttgccatggccactttggactcttccctgcaaattatgtcaagcttctggagtgactagagctcactgtctactgcaactgtgatttcccatgtccaaagtggctctgctccaccccctccctattcctgatgcaaatgtctaaccagatgagtttctggacagacttccctctcctgcttcattaagggcttggggcagagacagcatggggaaggaggtccccttccccaagagtcctctctatcctggatgagctcatgaacatttctcttgtgttcctgactccttcccaatgaacacctctctgccaccccaagctctgctctcctcctctgtgagctctgggcttcccagtttgtttacccgggaaagtacgtctagattgtgtggtttgcctcattgtgctatttgcccactttccttccctgaagaaatatctgtgaaccttctttctgttcagtccta75 202992_atgctggaatacttactcttgtcgggagattgaaccactaaaatgttagagcagaattcattatgctgtggtcacaggggtgtcttgtctgagaacaaatacaattcagtcttctctttggggttttagtatgtgtcaaacataggactggaagtttgcccctgttcttttttcttttgaaagaacatcagttcatgcctgaggcatgagtgactgtgcatttgagatagttttccctattctgtggatacagtcccagagttttcagggagtacacaggtagattagtttgaagcattgaccttttatttattccttatttctctttcatcaaaacaaaacagcagctgtgggaggagaaatgagagggcttaaatgaaatttaaaataagctatattatacaaatactatctctgtattgttctgaccctggtaaa76 202994_s_ataatgcgaaggctaagtgtcaccccctttctctgcctctggctgggccttgctaagggccaaggaaagaaagacattttttagggggcagccagtccaaatgccaaaagaagaccagttcttgccctgattgtatgaaatttgacattttggcactttttttttttttttnggccaatcagattttctatgttctaaggacatggctgctgtagaatagcacagacgtggatgataaattatccccagaagcagcatgacagaatgcctcggggagcacttggaagggaaattgcagttctgttgaaatagaggaaaatcccttggtaaagacacagcctgttaggctcgtgtgggcctccagtatgttcaccaggggaa 77 202995_s_ataacgatgtcacatgcgtgttcgaccccgtgcacaccatctcccacaccgtcatctcgctgcctaccttccgcgagttcacccgccctgaagagatcatcttcctccgggccatcacgccaccgcatcctgccagccaggctaacatcatcttcgacatcacggaagggaacctgcgggactcttttgacatcatcaagcgttacatggacggcatgaccgtgggtgtcgtgcgccaggtgcggcccatcgtgggcccatttcatgccgtcctgaagctggagatgaactatgtggtcgggggcgtggtttcccaccgaaatgttgtcaacgtccgcatcttcgtctctgagtactggttctgagggctggtctgccgcacagccgcaggtgcacctccaggccaaatcattgctgccagtgactgtggtctgtacttgtttataccctcag 78 203000_atgacagacctgagaccaatctgggtagaagcaaaaagttgaaccttttaaagtgctgaacacaaatccaaattcgaatggttcaagcagccgtgaaatcgctcttcataaagtgggcttaattctctagtttaagttcttttgatggaatgaattaattaatgtgtcaggtggcttatttgtggatgccatgattgatgatgttcattttaagctcttacctatagtacaagtacatgatgctactgaatatttttccacttggaaactgtgagctggttgttgcattaaaacacacatacaaacaaaatcaaaaacactgcggactttcactcaagctggtctttcttccccagtgtaaggcaatcctgcctactaacaacaccaacaacaaaacactccatctgtgaanntgacgcagttaagggggctaggcagggcatttgtgccaactaagaatcaccagatacccaccataagtacctatcgcagttttgaagtc 79203001_s_atacctcgcaacatcaacatctatacttacgatgatatggaagtgaagcaaatcaacaaacgtgcctctggccaggcttttgagctgatcttgaagccaccatctcctatctcagaagccccacgaactttagcttctccaaagaagaaagacctgtccctggaggagatccagaagaaactggaggctgcaggggaaagaagaaagtctcaggaggcccaggtgctgaaacaattggcagagaagagggaacacgagcgagaagtccttcagaaggctttggaggagaacaacaacttcagcaagatggcggaggaaaagctgatcctgaaaatggaacaaattaaggaaaaccgtgaggctaatctagctgctattattgaacgtctgcaggaaaaggagaggcatgctgcggaggtgcgcaggaacaaggaactccaggttgaactgtctggctgaagcaagggagggtctggcacgcc80 203058_s_atatggcctctgtgaataatgtaactccagttacacggtgacttttaatagcatacagtgatttgatgaaaggacgtcaaacaatgtggcgatgtcgtggaaagttatctttcccgctctttgctgtggtcattgtgtcttgcagaaaggatggccctgatgcagcagcagcgccagctgtaataaaaaataattcacactatcagactagcaaggcactagaactggaaaagaccacagaaaacaaagaatccaaccctttcatcttacaggtgaacaaactgtgatgatgcacatgtatgtgttttgtaagctgtgagcaccgtaacaaaatgtaaatttgccattattaggaaagtgctggtggcagtgaagaagcacccaggccacttgactcccagtctggtgccctgtctacaccagacaacacaggagctgggtcagattcccctcagctgcttaacaaagttcctcgaacagaaagtgcttacaaagctgccttctcggatact81 203060_s_atagctgccttctcggatactgaaaggtcgagttttctgaactgcactgattttattgcagttgaaaaacccaaagctattccaaagatttcaagctgttctgagacatcttctgatggctttacttcctgagaggcaatgtttttactttatgcataattcattgttgccaaggaataaagtgaagaaacagcacctttttaatatataggtctctctggaagagacctaaatttagaaagagaaaactgtgacaattttcatattctcattcttaaaaaacactaatcttaactaacaaaagttcttttgagaataagttacacacaatggccacagcagtttgtctttaatagtatagtgcctatactcatgtaatcggttactcactactgcctttaaaaaaaaccagcatatttattgaaaacatgagacaggattatagtgccttaaccgatatattttgtgacttaaaaaatacatttaaaactgctcttctgctctagtaccatgcttagtgcaaatgattatttctatgtacaactgatgcttgttcttattt 82 203066_atttcagttgctaatgaggctcctccgctctggacacaacccttttatagattaatttctctgccaattaacttgtcattttcagtacatattttactattccacaccaaccataattacaacaagggatttttcttatgcactcctatgcatgtgaataacatgtggtgtaattctgcttcttacagaagtattactgaaggtattatttccaatattatttggtttattatgcggatcttttttatatatgcagtcccatcccttctgtgccactcaatgccatccagacatggtttttccctccaggggcctttctctccagagggcacttcggctgcctctgcttcctctcattcgaggcccggctcttgctgacagaataggttccgttctgggcggtggttctcgagcctgccattcaaaaccaaagcaaattggagcatttctcacaacatggtattgaagttcctttttgttctcaaaagttgtgaccgtgttaaattgtactcccttagtcctgtaaggtatgttaagtgaatcgcagttacgctgtactttta83 203131_atagaaaatttgccaatctttcctactttctatttttatgatgacaatcaaagccggcctgagaaacactatttgtgactttttaaacgattagtgatgtccttaaaatgtggtctgccaatctgtacaaaatggtcctatttttgtgaagagggacataagataaaatgatgttatacatcaatatgtatatatgtatttctatatagacttggagaatactgccaaaacatttatgacaagctgtatcactgccttcgtttatatttttttaactgtgataatccccacaggcacattaactgttgcacttttgaatgtccaaaatttatattttagaaataataaaaagaaagatacttacatgttcccaaaacaatggtgtggtgaatgtgtgagaaaaactaacttgatagggtctaccaatacaaaatgtattacgaatgcccctgttcatgtt 84 203240_atccaggactacagaataccatcccctggtaccgtgtagttgccgaagtccagatctgccatggcaaaacggaggctgtgggccaggtccacatcttcttccaggatgggatggtgacgttgactccaaacaagggtgtgtgggtgaatggtctccgagtggatctcccagctgagaagttagcatctgtgtccgtgagtcgtacacctgatggctccctgctagtccgccagaaggcaggggtccaggtgtggcttggagccaatgggaaggtggctgtgattgtcagcaatgaccatgctgggaaactgtgtggggcctgtggaaactttgacggggaccagaccaatgattggcatgactcccaggagaagccagcgatggagaaatggagagcgcaggacttctccccatgttatggctgatcagtcatccaccaggaacgaagatttcctgaagaagacctggtccctctggaggttgcggtggctgaaggatgcatcatgtgctcctaccctgctctaccgcttttctgggtcacagag 85 203296_s_ataaagacaagcattgggtcagacccataaaccacctcccaaaggctgtcatttcattgcactggaattttgctttatcagaagcaaggaagtaagggagtcattgccttgggcctgggaatctaagtgggagacaatattaatttggatccgattaattggagattactaactgtggacaaaagtttatctttgcacaatcaataaaaatggcatttttttagtaaattaagagcataaacaatattgctagaggtggcatgtttagtctaccaaaaacaatacttttcaggcactttagaaatatccttttagaagcagcgagtgcatgggctaattatcatcaatctttatgtatttgttaaagaaacatctacaggatctttattggtgaccttttgta86 203305_atgtccttcacatcaccattttgagacctcagcttggcactcaggtgctgaagggtaatatggactcagccttgcaaatagccagtgctagttctgacccaaccacagaggatgctgacatcatttgtattatgttccaaggctactacagagaaggctgcctgctatgtatttgcaaggctgatttatggtcagaatttccctctgatatgtctagggtgtgatttaggtcagtagactgtgattcttagcaaaaaatgaacagtgataagtatactgggggcaaaatcagaatggaatgctctggtctatataaccacatttctgagcctttgagactgttcctgagccttcagcactaacctatgagggtgagctggtcccctctatatatacatcatacttaactttactaagtaatctcacagcatttgccaagtctcccaatatccaatt 87 203343_atatgtgtcactgattttttagctcaaaatcatcactgttaatttccagtcaccccaaatatggttaaaagatttttttttttaatcatgaagagaaaattagtagcatttctttctctccccattatttattggttttcctcactaatctttttttttttagtccaaaagccaaaaatatttatcttggttttacattttaatttccattcttaattgtaatttttttctttaaataaggaaaccaatataatctcatgtataaaaacttaaatattttacaagttacatatagcatcattctaaaataagaattttttttgttttctgtctgcttttttcttatgtctcttgttgagttttatattttcagtggttatttttgcttgtgttagatcattattaaaatatatccaatgtccctttgatacttgtgctctgctgagaatgtacagtttgcattaaacatcccaggtctcatccttcaggaattt 88 203382_s_atgaagcgcctggcagtgtaccaggccggggcccgcgagggcgccgagcgcggcctcagcgccatccgcgagcgcctggggcccctggtggaacagggccgcgtgcgggccgccactgtgggctccctggccggccagccgctacaggagcgggcccaggcctggggcgagcggctgcgcgcgcggatggaggagatgggcagccggacccgcgaccgcctggacgaggtgaaggagcaggtggcggaggtgcgcgccaagctggaggagcaggcccagcagatacgcctgcaggccgaggccttccaggcccgcctcaagagctggttcgagcccctggtggaagacatgcagcgccagtgggccgggctggtggagaaggtgcaggctgccgtgggcaccagcgccgcccctgtgcccagcgacaatcactgaacgccgaagcc 89 203474_atactgtgatataggtactctgatttaaaactttggacatcctgtgatctgttttaaagttggggggtgggaaatttagctgactagggacaaacatgtaaacctattttcctatgaaaaaagttttaaatgtcccacttgaataacgtaattcttcatagtttttttaatctatggataaatggaaacctaattatttgtaatgaattatttagacagttctaagccctgtcttctgggagttatcaattttaaagagaacttttgtgcaattcaaatgaagtttttataagtaattgaaaatgacaacacaataacactttctgtataaaagtatatattttatgtgatttattcctactaaatgaaagtgcactactgcctcatgtaaagactcttgcacgcagagcctttaagtgactaaggaacaacatagatagtgagcatagtccccacctccacccctcacaatttatttgaatacttcaattgtgcctctcaa 90 203477_atttcagacagttatatcctccttttaaaccattgttgttgagtgtaagatgtccttcatgttttcttataaagtcagtgtttagaaatgttaccctttctaagttatatacagatcaaatgcttttttctttcacgtacatccatcatttgcaactgctgttcgtacacagaaacaggactgctcaaatgatcctatttgtattttctgatgctatcagactctaatgtttttttccctaaaatattattgccatcatgctttaggaatttttatatttttacacaatcatattttagtatggtgtctgtttatgtaactctgacttgctggaaaagttgaaactccaaataatctgaaactagaaaagaaatagcacataattactaccttccccttggcggctctcctcccccaacccccaccccacaattttatgacttcca91 203638_s_atcaacgtctaactggacttcccaagataaatggtaccagcgtcctcttaaaagatgccttaatccattccttgaggacagaccttagttgaaatgatagcagaatgtgcttctctctggcagctggccttctgcttctgagttgcacattaatcagattagcctgattctcttcagtgaattttgataatggcttccagactctttgcgttggagacgcctgttaggatcttcaagtcccatcatagaaaattgaaacacagagttgttctgctgatagttttggggatacgtccatctttttaagggattgctttcatctaattctggcaggacctcaccaaaagatccagcctcatacctacatcagacaaaatatcgccgttgttccttctgtactaaagtattgtgttttgctttggaaacacccactcact92 203645_s_atgccagacgctggggccatagtgagtgtgggcacaaggaagacgctgcagtgaattgcacagatatttcagtgcagaaaaccccacaaaaagccacaacaggtcgctcatcccgtcagtcatcctttattgcagtcgggatccttggggttgttctgttggccattttcgtcgcattattcttcttgactaaaaagcgaagacagagacagcggcttgcagtttcctcaagaggagagaacttagtccaccaaattcaataccgggagatgaattcttgcctgaatgcagatgatctggacctaatgaattcctcaggaggccattctgagccacactgaaaaggaaaatgggaatttataacccagtgagttcagcctttaagataccttgatgaagacctggactattgaatggagcagaaattcacctctctcactgactattacagttgcatttttatggagttcttcttctcctaggattcc 93203680_atttttcattgttcattgatatgctcagtatgctgccacataagatgaatttaattatattcaaccaaagcaatatactcttacatgatttctaggccccatgacccagtgtctagagacattaattctaaccagttgtttgcttttaaatgagtgatttcattttgggaaacaggtttcaaatgaatatatatacatgggtaaaattactctgtgctagtgtagtcttactagagaatgtttatggtcccacttgtatatgaaaatgtggttagaatgttaattggataatgtatatataagaagttaaagtatgtaaagtataacttcagccacatttttagaacactgtttaacatttttgcaaaaccttcttgtaggaaaagagagctctctacatgaagatgacttgttttatatttcagattttattttaaaagccatgtctgttaaacaagaaaaaacacaaaagaactccagattcctggttcatcattctgtattcttactcactttttcaagtt 94203729_atatcctcattcttatactgcttttcgtggccactttggacaagtcctggtggactctccctgggaaagagtccctgaatctctggtacgactgcacgtggaacaacgacaccaaaacatgggcctgcagtaatgtcagcgagaatggctggctgaaggcggtgcaggtcctcatggtgctctccctcattctctgctgtctctccttcatcctgttcatgttccagctctacaccatgcgacgaggaggtctcttctatgccaccggcctctgccagctttgcaccagcgtggcggtgtttactggcgccttgatctatgccattcacgccgaggagatcctggagaagcacccgcgagggggcagcttcggatactgcttcgccctggcctgggtggccttccccctcgccctggtcagcggcatcatctacatccacctacggaagcgggagtgagcgccccgc 95 203748_x_atcaagtatcggggctctgctatcaaggtgcaaagtccttcgtggatgcaacctcaaccatatattctacagcaccctggtgccgtgttaactccctcaatggagcacaccatgtcactacagcccgcatcaatgatcagccctctggcccagcagatgagtcatctgtcactaggcagcaccggaacatacatgcctgcaacgtcagctatgcaaggagcctacttgccacagtatgcacatatgcagacgacagcggttcctgttgaggaggcaagtggtcaacagcaggtggctgtcgagacgtctaatgaccattctccatatacctttcaacctaataagtaactgtgagatgtacagaaaggtgttcttacatgaagaagggtgtgaaggctgaacaatcatggatttttctgatcaattgtgctttaggaaattattgacagttttgcacaggttcttgaaaacgttatttataatgaaatcaactaaaactatttttgctataagttctataaggtgcataaaacccttaaattcatctagtagctgttccccc 96 203766_s_atcaccttgggtctgtgtcacttgtaggtttctctgcctccaggttgcctcaacagcaggaggcacagcagtttcaccatctttgaggtgagggtggggtgccccagctaggaagcaagatcgctgtgctaggtctgaccaaaaccagagggcagtctagtcctgggggtaaagccctcagatcccagggtacactcttctccattccctccacccacttgcctgtcaccccagtcacctaagcaatcactgggcccagaggagaggagacagacacacactggctcctggacctaaagggtatgagctggagctaaggccagctagagcttccactgtcagccctcactgtcagccccactgcacccccctgtgcctgctgggcactgggcactagctagatgctttaggttgcttcagctgatccttcaactctgtgaggtg 97 203881_s_attatgtgacgctggaccttttctttacccaaggatttttaaaactcagatttaaaacaaggggttactttacatcctactaagaagtttaagtaagtaagtttcattctaaaatcagaggtaaatagagtgcataaataattttgttttaatctttttgtttttcttttagacacattagctctggagtgagtctgtcataatatttgaacaaaaattgagagctttattgctgcattttaagcataattaatttggacattatttcgtgttgtgttctttataaccaccgagtattaaactgtaaatcataatgtaactgaagcataaacatcacatggcatgttttgtcattgttttcaggtactgagttcttacttgagtatcataatatattgtgttttaacaccaacactgtaacatttacgaattatttttttaaacttcagttttactgcattttcacaacatatcagacttcaccaa 98 203908_attgtgtaatacgccaaccagtcaagttgtgttttggccagagatttagatatgtccaatttcctggctcatttcattgtgctctatgggtacgtataaaaagcaagaattctgtttcctaggcaaacattgcaactcagggctaaagtcatccagtgaaacttttagagccagaagtaactttgtcccagtcctacaatgtgaaaagagtgaatagttgcctctttttagccattttcatggctggtacatattcgtacgcattacttttcagaatcaatacgcactttcagatattcttatttttattctcttaagtctttattaactttggagagagaaatgatgcatctttttattttaaatgaagtagatcaacatggtggaacaaaatgataaagaacagaaaacatttcaatatattactaataactttttccaatataaatcctaaaattcctataacatagtattttacagttttatgaagctttctattgtgacttttatg 99203913_s_ataacactcacatacaagttcatactttaaaagaggaaagctacttaacaatgacaaatatttcacaataataatttttacttatataccatctttcaactgaacatttcagttcttccaagagcttcttagagtagtatattttgggggcagtcaaggaataaactacagtgtaaacatatcccagatgaaaactgctgtatggaaaaatgacagaaagtaactgattgacactgttgattcacagttcangcctcctatctgggaaagacatttctttcctctgctcactttaagaacttttaccgactccaaaaatctcaggaattaaacttttaacagttacagcaataaagaatagttagtactccaaaaatattatatttaagatgctcaacaagaaaaaaatgcaaatgtaatatttttttcaaattacttctttattgacttgtcca 100 203914_x_atgatttccaaatcagtcgttttctcaaaaaaatatcgtataagtgactcatcctgtctgctaactccagacctcccagcttgaagccaaatctttccatgtgagattgatatggatttcctagaagtactggaatgttgtcatatcttgccctattttaattctgctatagaaaacaattgccttcacttttaaggagtaatttgaatattaataactctggtctagattttcatataatgtattaaagacaaagtagtgaacatcaatgaacatctgatagagataaactgtaatcaggcataagcttgtttgtatgttctggcagtgactaatcagtaaatgatgtcggtttgcccagtatcacttatcttctgtatttttcctctgtcgtgtaaatagtataaccttttcatttatggacaattttttggactagtagccttcaatatacattctgctt 101 203951_atacgcacacaactactacaattccgcctaggtccacaaggccttcactgttttccccccaagggaggctgctgctgctcttggctggagccagccagggccagccgaccccctctccctgcatggcatcctccagcccctgtagaactcaacctctacagggttagagtttggagagagcagactggcggggggcccattggggggaaggggaccctccgctctgtagtgctacagggtccaacatagaacagggtgtccccaacagcgcccaaaggacgcactgagcaacgctattccagctgtccccccactccctcacaagtgggtacccccaggaccagaagctcccccagcaaagcccccagagcccaggctcggcctgcccccaccccattcccgcagtgggagcaaactgcatgcccagagacccagcggacacacgcggtttggtttgcagcgactggcatac 102203963_atccaaatttcatttcagccacttctgcaggatccctactgccaacctggaatggagacttttatctacttctctctctctgaagatgtcaaatcgtggtttagatcaaatatatttcaagctataaaagcaggaggttatctgtgcagggggctggcatcatgtatttaggggcaagtaataatggaatgctactaagatactccatattcttccccgaatcacacagacagtttctgacaggcgcaactcctccattttcctcccgcaggtgagaaccctgtggagatgagtcagtgccatgactgagaaggaaccgacccctagttgagagcaccttgcagttccccgagaactttctgattcacagtctcattttgacagcatgaaatgtcctcttgaagcatagctttttaaatatctttttccttctactcctccctctgactctaagaattctctcttctggaatcgcttg 103 203980_atgtgtgatgcttttgtaggtacctggaaacttgtctccagtgaaaactttgatgattatatgaaagaagtaggagtgggctttgccaccaggaaagtggctggcatggccaaacctaacatgatcatcagtgtgaatggggatgtgatcaccattaaatctgaaagtacctttaaaaatactgagatttccttcatactgggccaggaatttgacgaagtcactgcagatgacaggaaagtcaagagcaccataaccttagatgggggtgtcctggtacatgtgcagaaatgggatggaaaatcaaccaccataaagagaaaacgagaggatgataaactggtggtggaatgcgtcatgaaaggcgtcacttccacgagagtttatgagagagcataagccaagggacgttgacctggactgaagttcgcattgaactctacaacattctgtgggatatattgttcaaaaagatattgttgttttccctgatttagcaagca104 204018_x_atggtccccacagactcagagagaacccaccatggtgctgtctcctgccgacaagaccaacgtcaaggccgcctggggtaaggtcggcgcgcacgctggcgagtatggtgcggaggccctggagaggatgttcctgtccttccccaccaccaagacctacttcccgcacttcgacctgagccacggctctgcccaggttaagggccacggcaagaaggtggccgacgccctgaccaacgccgtggcgcacgtggacgacatgcccaacgcgctgtccgccctgagcgacctgcacgcgcacaagcttcgggtggacccggtcaacttcaagctcctaagccactgcctgctggtgaccctggccgcccacctccccgccgagttcacccctgcggtgcacgcctccctggacaagttcctggcttctgtgagcaccgtgctgacctccaaataccgttaagctg 105 204034_atgcccaggctgacttacacattgaggatggagactccatccgcttcgggcgcttcgcgttggagaccagggccagccctggccacaccccaggctgtgtcaccttcgtcctgaatgaccacagcatggccttcactggagatgccctgttgatccgtgggtgtgggcggacagacttccagcaaggctgtgccaagaccttgtaccactcggtccatgaaaagatcttcacacttccaggagactgtctgatctaccctgctcacgattaccatgggttcacagtgtccaccgtggaggaggagaggactctgaaccctcggctcaccctcagctgtgaggagtttgtcaaaatcatgggcaacctgaacttgcctaaacctcagcagatagactttgctgttccagccaacatgcgctgtggggtgcagacacccactgcctgatctcacttctgtcagatgctcccatccactattaatgcactaggtgggaggagagggcggcaatgacactgcacct106 204036_ataattgccacattttcttatggcattaaaaattttacaaaaacataattttaatggctatattatattccatttaatggatgcaactcangtttatttaaccattcccatngttgttaactatttaggttgtttctaattttcattattataaagttgcagaaatttggtgtacataaaactgtctccatataattgattattaggatatattcccatgaaggattcntttttttaaaaaaatgtgaaatntcatcttgtacttacacctttcatgnaaagggatttcctgcttttgtactgcatgggtggcagttgtgaggaaaagccagtcaaatgacctttttacaaaagaaatgcagtggtcacttcagttgagagtgactttttaatacaacaagatcaactagaagaattcaactgtctcaagaatcaaggtaccccaatatatctcgcaattccaaactttgtttgagggactcgttatccagctcttggtagccacacctgcaatgta 107204069_ataagccttacagttatcctgcaagggacaggaaggtctgatttgcaggatttttagagcattaaaataactatcaggcagaagaatctttcttctcgcctaggatttcagccatgcgcgcgctctctctctttctctctcttttcctctctctccctctttctagcctggggcttgaatttgcatgtctaattcatttactcaccatatttgaattggcctgaacagatgtaaatcgggaaggatgggaaaaactgcagtcatcaacaatgattaatcagctgttgcaggcagtgtcttaaggagactggtaggaggaggcatggaaaccaaaaggccgtgtgtttagaagcctaattgtcacatcaagcatcattgtccccatgcaacaaccaccaccttatacatcacttcctgttttaagcagctctaaaacatagactgaagatttatttttaatatgttgactttatttctgagcaaagcatcggtcatgtgtgtattttttcatagtcccaccttggagcatttatg108 204083_s_atgaaggcggctgatgagagcgagagaggaatgaaggtcatcgaaaaccgggccatgaaggatgaggagaagatggaactgcaggagatgcagctgaaggaggccaagcacatcgctgaggattcagaccgcaaatatgaagaggtggccaggaagctggtgatcctggaaggagagctggagcgctcggaggagagggctgaggtggccgagagccgagccagacagctggaggaggaacttcgaaccatggaccaggccctcaagtccctgatggcctcagaggaggagtattccaccaaagaagataaatatgaagaggagatcaaactgttggaggagaagctgaaggaggctgagacccgagcagagtttgccgagaggtctgtggcaaagttggagaaaaccatcgatgac 109 204122_atcatggggggacttgaaccctgcagcaggctcctgctcctgcctctcctgctggctgtaagtggtctccgtcctgtccaggcccaggcccagagcgattgcagttgctctacggtgagcccgggcgtgctggcagggatcgtgatgggagacctggtgctgacagtgctcattgccctggccgtgtacttcctgggccggctggtccctcgggggcgaggggctgcggaggcagcgacccggaaacagcgtatcactgagaccgagtcgccttatcaggagctccagggtcagaggtcggatgtctacagcgacctcaacacacagaggccgtattacaaatgagcccgaatcatgacagtcagcaa 110 204130_attccccagcagtggctcggtgagccatgtgcacctatggcccagccactgcagcacaggaggctccgtgagccttggttcctccccgaaaacccccagcattacgatcccccaagtgtcctggaccctggcctaaagaatcccacccccacttcatgcccactgccgatgcccaatccaggcccggtgaggccaaggtttcccagtgagcctctgcgcctctccactgtttcatgagcccaaacaccctcctggcacaacgctctaccctgcagcttggagaactccgctggatgggagtctcatgcaagacttcactgcagcctttcacaggactctgcagatagtgcctctgcaaactaaggagtgactaggtgggttggggaccccctcaggattgtttctcggcaccagtgcctcagtgctgcaattgagggctaaatcccaagtgtctcttgactggctcaagaattagggcccca 111204135_atcagaccggcagtcatcatggcagtttcagcgttcaaacagcaatagctcaagtgtgataactactgaggataataaaatccacattcacttaggaagtccttacatgcaagctgtagccagcccttcagcaccactgcaggataaccgaactcaaggcttaattaacggggcactaaacaaaacaaccaataaagtcaccagcagtattactatcacaccaacagccacacctcttcctcgacaatcacaaattacagtaagtaatatatataactgaccacgctcaccctcatccagtccatactgatatttttgcaaggaactcaatccttttttaatcatccctccatatcccccaagactgactgaactcgtactttgggaaggtttgtgcatgaactatacaagagtatctgaaactaactgttgcctgcatagtcatatcgagtgtgcacttactgtatatcttttcat 112 204326_x_atgcgtgttttcctcttgatcgggaactcctgcttctccttgcctcgaaatggaccccaactgctcctgctcgcctgttggctcctgtgcctgtgccggctcctgcaaatgcaaagagtgcaaatgcacctcctgcaagaagagctgctgctcctgctgccctgtgggctgtgcnaagtgtgcccagggctgcatctgcaaagggacgtcagacaagtgcagctgctgtgcctgatgccaggacagctgtgctctcagatgtaaatagagcaacctatataaacctggatttttttttttttttttttgtacaaccctgacccgtttgctacatctttttttctat 113 204388_s_atttccacatcagtaactgccctggggtttgtgctgtacaaatacaagctcctgccacggtcttgaagttctgttcttatgctctctgctcactggttttcaataccaccaagaggaaaatattgacaagtttaaaggctgtgtcattgggccatgtttaagtgtactggatttaactacctttggcttaattccaatcattgttaaagtaaaaacaattcaaagaatcacctaattaatttcagtaagatcaagctccatcttatttgtcagtgtagatcaactcatgttaattgatagaataaagccttgtgatcact114 204389_atctttgcgggcacagagactgccacaaagtggagcggctacatggaaggggcagttgaggctggagaacgagcagctagggaggtcttaaatggtctcgggaaggtgaccgagaaagacatctgggtacaagaacctgaatcaaaggacgttccagcggtagaaatcacccacaccttctgggaaaggaacctgccctctgtttctggcctgctgaagatcattggattttccacatcagtaactgccctggggtttgtgctgtacaaatacaagctcctgccacggtcttgaagttctgttcttatgctctctgctcactggttttcaataccaccaagaggaaaatattgacaagtttaaaggctgtgtcattgggccatgtttaagtgtactggatttaactacctttg115 204438_attaattgcttgttttctagcctggcaagatattttcataaaagagggataacaatgctgattactaccttttaaaatattttagataaatgcacagcaccacagcaccacatctaagcattagtgatgggtagctgatgtcagcttcatgtggattttaagcactctagaaacaatgaagcttcttggcatattttaaggagctcccaaaatgtgttacctattaaattgtaactcagcaagtagaagaccatttgaaaagtcaggtacaaatttcctcaagtggcataaaaatgtagtcagttttctcttttaccagtttttatttccactccaattatttagaactttatttgtacatgtgcagaagaataaggcagctgagaatcttgtttcccccaagagagttttacaggctgagtgttgcaaatgtgttctttgtcctgttatatgtat 116 204457_s_atgcactgccatgtatgaaagtctctttatgatgtttgtttttttgtcatttttgttctttacatcaagaaattttatgtttaaatatgcggagaatgtatattgcctctgctcctatcagggttgctaaaccctggtacatcgtatataaaatgtattaaaactggggtttgttaccagttgctgtactttgtatatagaatttttataaattgtatgcttcagaaataatttatttttaaaaagaaattaaaagttttaaactcacatccatattacacctttcccccctgaaatgtatagaatccatttgtcatcaggaatcaaaacccacagtccattgtgaagtgtgctatatttagaacagtcttaaaatgtacagtgtattttatagaattgaagttaacattcttattttcaagagaatttatggacgttgtagaaatgtacaaatgcatttccaaactgccttaaacgttgtatt 117 204508_s_atgggactgtctgtcaaaagactctgtatatcttttgtggatgagttttgtgagagaacagagagaccattgtacctggcacaagggctcttcatgaaaagggagacttactgggaggtgcaagacagtggcatttctcctctcctcttgctgctcagcacagccctggattgcagccccgaggctgagaccagacaaagcccgggaggcagaaagatgctccaagaaccaacactatcaatgtctttgcaaatcctcacaggattcctgtgggtccagctttggaactgggaaacctttcttcggatccgcactcattccactgatgccagctgcccctgaaggatgccagtactgtggtgtgtgagtctcagcagccgcccacacgctcctaactctgctgcatggcagatgcctaggtgga118 204532_x_atattaatcagccccagagtgctttaaaaaattctcttaaataaaaataatagactcgctagtcagtaaagatatttgaatatgtatcgtgccccctccggtgtctttgatcaggatgacatgtgccatttttcagaggacgtgcagacaggctggcattctagattacttttcttactctgaaacatggcctgtttgggagtgcgggattcaaaggtggtcccaccgctgcccctactgcaaatggcagttttaatcttatcttttggcttctgcagatggttgcaattgatccttaaccaataatggtcagtcctcatctctgtcctgcttcataggtgccaccttgtgtgtttaaa 119 204570_atctacgcgtgtccttgggcggagaagggaggtgactccggcggaagaggacaaggcagaatgcaggcccttcgggtgtcccaggcgctgatccgctccttcagctccaccgcccggaaccgctttcagaaccgagtgcgcgagaaacagaagctcttccaggaggacaatgacatcccgttgtacctgaagggcggcatcgttgacaacatcctgtaccgagtgacaatgacgctgtgtctgggcggcactgtctacagcttgtactcccttggctgggcctccttccccaggaattaagaccaagaagcctggggggcctgagagact 120 204607_attggtgacacaaacagccttttcccaggtacttggtacctggagcgagtggacgagcagcatcgccgaaagtatgcccggcgtcccgtctaaaggtgttctgcagatccatggaaagcttcctgggaaacgtatgctagcagagcttctccccgtgaatcatatttttaagatcccactcttagctggtaaatgaatttgaatcgacatagtagccccataagcatcagccctgtagagtgaggagccatctctagcgggcccttcattcctctccatgctgcaatcactgtcctgggcttatggtgcctatggactaggggtcctttgtgaaagagcaagatggagcaatggagagaagacctcttcctgaatcactggactccagaaatgtgcatgcagatcagctgttgccttca121 204673_atttgatgccagcatttgcatcccgggctccatcacattcatgcccaatggatgctgcaagacctgcacccctcgcaatgagaccagggtgccctgctccaccgtccccgtcaccacggaggtttcgtacgccggctgcaccaagaccgtcctcatgaatcattgctccgggtcctgcgggacatttgtcatgtactcggccaaggcccaggccctggaccacagctgctcctgctgcaaagaggagaaaaccagccagcgtgaggtggtcctgagctgccccaatggcggctcgctgacacacacctacacccacatcgagagctgccagtgccaggacaccgtctgcgggctccccaccggcacctcccgccgggcccggcgctcccctaggcatctggggagcgggtgagcggggtgggcacagcccccttcactgccctcgacagctttacctcccccggaccctctgagcctcctaagctcggcttcctctcttcagatatttattgtctgagtctttgttcagtccttg 122 204688_atcttgcttatatcatgtgctgccgacgggaaggcgtggaaaagagaaacatgcaaacaccagacatccaactggtccatcacagtgctattcagaaatctaccaaggagcttcgagacatgtccaagaatagagagatagcatggcccctgtcaacgcttcctgtgttccaccctgtgactggggaaatcatacctcctttacacacagacaactatgatagcacaaacatgccattgatgcaaacgcagcagaacttgccacatcagactcagattccccaacagcagactacaggtaaatggtatccctgaagaaagaaaactgactgaagcaatgaatttataatcagacaatatagcagttacatcacatttcttttctcttccaataatgcatgagcttttctggcatatgtt123 204697_s_atcctcccgggaggacagccttgaggcgggcctgcccctccaggtccgaggctaccccgaggagaagaaagaggaggagggcagcgcaaaccgcagaccagaggaccaggagctggagagcctgtcggccattgaagcagagctggagaaagtggcccaccagctgcaggcactacggcggggctgagacaccggctggcagggctggccccagggcaccctgtggccctggctctgctgtccccttggcaggtcctggccagatggcccggacgctgcttccggtagggaggcagcctccagcctgcccaagcccaggccaccctatcgccccctacgcgccttgtctcctactcctgactcctacctgccctggaacatcctttgcagggcagccccacaactttaaacattgacgattccttctctgaacacaggcagctttctagaagtttcccttcctccatcctatccactgggcacaactgcaataacttctgaccttttggtgaaagctgagaactcctgactgtaacatattctg 124 204719_atgcaggccatactggttccattgttctgtataatactgaataaataaatttacttttacatgatcgtataagtttctagataagataaacaaattctgtttaaatttttttaataaaaatcttaaaacactttttttctaacctagactgagaaattcatgtttacttttctaggtgtatgatactttgtaaagttgatactttcctaagaatttaacatgtcatatttttgaaatagatttaagtgtgcttcttattgctaaaaatactaaatgtcatgggtcatagtatctgatatcaatatcgttgataacatatccacaggtaacaccatgatgtaggcataaatggaaaacaaaaaccctactatttcaaatatattgtacttttttatttctgtaagccaactgtgtgccattttcactggacttttaaatctagactttagtgatgtctacattgtaaatgatcttttgtggatatttgtcacttggtttcagaaagttcacaaatgtagcaacagctcacatgactgagt125 204745_x_attcccttctcgcttgggaactctagtctcgcctcgggttgcaatggaccccaactgctcctgtgccgctggtgtctcctgcacctgcgccagctcctgcaagtgcaaagagtgcaaatgcacctcctgcaagaagagctgctgctcctgctgccctgtgggctgtgccaagtgtgcccaaggctgcatctgcaaaggggcatcggagaagtgcagctgctgcgcctgatgtcgggacagccctgctcccaagtacaaatagagtgacccgtaaaatctaggattttttgttttttgctacaatcttgacccct126 204818_ataaaggctggcatcttatggctcatcaaaggcggctgtgaccatgttctcatcagttatgagactggagctttccaagtggggaattaaagttgcttccatccaacctggaggcttcctaacaaatatcgcaggcaccagtgacaagtgggaaaagctggagaaggacattctggaccacctccccgctgaggtacaggaagactacggccaggactacatcttagcacagcggaatttcctcctattgatcaactcgttagccagcaaggacttctctccggtgctgcgggacatccagcatgctatcttggcgaagagcccttttgcctattacacgccagggaaaggcgcttacttgtggatctgccttgctcactatttgcctattggca127 204834_atggtgtcgaactatatgccttgtatgatcagttttatgtggctaatgagtttctcaaatatcgtttacacgttggtaactataatggcacagctggagatgcattacgtttcaacaaacattacaaccacgatctgaagtttttcaccactccagataaagacaatgatcgatatccttctgggaactgtgggctgtactacagttcaggctggtggtttgatgcatgtctttctgcaaacttaaatggcaaatattatcaccaaaaatacagaggtgtccgtaatgggattttctggggtacctggcctggtgtaagtgaggcacaccctggtggctacaagtcctccttcaaagaggctaagatgatgatcagacccaagcactttaagccataaatcactctgttcattcctccaggtattcgttatctaatagggcaattaattccttcagcacttt 128 204894_s_atccaggaggggctgtccaatcacattcaggcatgcgaatgagctgggccctgggtgaggtgggggtctggcctagtggggaggggcctggcctgggtggggcagggcctggcctggtccaggcttgggctccattcccatcactgctgtccctcctgaggtctggattggggatggggacaaagaaatagcaagagatgagaaacaacagaaacttttttctctaaaggactggttaaatcaattctgatacagccttacaatacaatagtatgcagctaaaaaataattgtatgtctttatatactaatatgtaataatcttcaggtgaaaaaggcaagccacagaaatgtgtatagcgcacttcccatttgtgtttcagaaaggagtagaatataaacacataattgcttatgtatgcctattcagaataaatgggtaacactgattacttttgggaggggaaccagtaggttgaggacaggagagggaagggtcttaacacttacacccttttgtacattttg129 204895_x_ataggagcccaggaacgacgtggtcttccagcccatttccggggaagacgtgcgcgatgtgacagccctgaacgtgagcacgctgaaggcttacttcagatgcgatggctacaagggctacgacctggtctacagcccccagagcggcttcacctgcgtgtccccgtgcagtaggggctactgtgaccatggaggccagtgccagcacctgcccagtgggccccgctgcagctgtgtgtccttctccatctacacggcctggggcgagcactgtgagcacctgagcatgaaactcgacgcgttcttcggcatcttctttggggccctgggcggcctcttgctgctgggggtcgggacgttcgtggtcctgcgcttctggggttgctccggggccaggttctcctatttcctgaactcagctgaggccttgccttgaaggggcagctgtggcctaggctacctcaagactcacctcatccttaccgcacatttaaggcgccattgcttttgggagact130 204897_atagcagcttattgtttctctgaaagtgtgtgtagttttactttcctaaggaattaccaagaatatcctttaaaatttaaaaggatggcaagttgcatcagaaagctttattttgagatgtaaaaagattcccaaacgtggttacattagccattcatgtatgtcagaagtgcagaattggggcacttaatggtcaccttgtaacagttttgtgtaactcccagtgatgctgtacacatatttgaagggtctttctcaaagaaatattaagcatgttttgttgctcagtgtttttgtgaattgcttggttgtaattaaattctgagcctgatattgatatg131 204931_atgagaacgggtacattcacccggtcaacctgacgtggccctttatggtggccgggaaacccgagagtgacctgaaagaagtggtgaccgcgagccgcttatgtggaaccaccgcgtcctgaccttggaggtgcgagtctgggaaaggcgcgctcccggggggagcgggccccgggaaggcgacccctgccctcagtgctctctgtctctgcttccccctcgcaatgctcctctctctgtcccaccccgcgagaacactttacaacgacgaggagattcgtttccaaaccagaggagatcaattgtacttacaaagattcccatctatttaactttattaacttctaccgtgaatgactctgcaagccttgctggtcca 132204938_s_atttctctcgaccacttaaaacttcagacttcctgtcctgctggtatcatggagaaagtccaatacctcactcgctcagctataagaagagcctcaaccattgaaatgcctcaacaagcacgtcaaaagctacagaatctatttatcaatttctgtctcatcttaatatgtctcttgctgatctgtatcatcgtgatgcttctctgaagttctgctacaacctctagatctgcagcttgccacatcagcttaaa 133 204939_s_attggcccatctattacatctacagctgacccttgaacatgggggttaggggagctgacaattcgtgggtccgcaaaatcttaactacctaatagcctactattgaccataaaccttactgataacataaacagtaaattaacacatattttgcgtgttatatgtattatacactatattcctacaataaagt134 204940_ataaatctgttctaagacatatgatcaacagatgagaactggtggttaatatgtgacagtgagattagtcatatcactaatatactaacaacagaatctaatcttcatttaaggcactgtagtgaattatctgagctagagttacctagcttaccatactatatctttggaatcatgaaaccttaagacttcagaatgattttgcaggttgtcttccattccagcctaacatccaatgcaggcaaggaaaataaaagatttccagtgacagaaaaatatattatctcaagtattttttaaaaatatatgaattctctctccaaatattaactaattattagattatattttgaaatgaacttgttggcccatc 135 204955_atggacaaagagcgctatgtctccctggtgatgcctgtggccctgttcaacctgattgacacttttcccttgagaaaagaagagatggtcctacaagccgaaatgagccagacctgtaacacctgacatgatggttcctctcttggcaattcctcttcattgtctacatagtgacatgcacacgggaaagccttaaaaatatccttgatgtacagattttatttgtaattttaaaagtctattttattatgagctttctttgcacttaaaaattagcatgctgctttttgtacttggaagtgtttcaaaaaattatatgaccatatttactctttctaacctttctttactccatcatggctggttgatttgtagagaaattagaacccataaccatacacaggctatcaacatgttattcaatgtgacacctaactcttttc136 205097_attactcatgcctttttgtttaggataaataggtaagcacaaagagctcttcaaaatcagaaaaaacaataggagtccttccttgtcttttctgtgatctctgtccttgtttctgagactttctctaccattaagctctattttagctttcagttattctagtttgtttcccatggaatctgtcctaaactggtgtttttgtcagtgacagtcttgccagtcagcaatttctaacagcattttaaatgagtttgatgtacagtaaatattgatgacaatgacagcttttaactcttcaagtcacctaaagctattatgcaggaggatttagaagtcacattcataaaacccaagngctatgggtgtattattcatgatagctggcccacaggtcatgaattgag 137205112_atagaagctcaccaagtcaactaaacagccccgaggacttacatcaccttctcagctcttgacctcagaaagtatccaaaccaaggaggagaaacctgtgggtggcttgtcctccagtgacacaatggattaccgacagtgactaagggcagcatgtttaacccaggtgaagatct138 205200_attttctggccttcacccagacgaagaccttccacgaggccagcgaggactgcatctcgcgcgggggcaccctgagcacccctcagactggctcggagaacgacgccctgtatgagtacctgcgccagagcgtgggcaacgaggccgagatctggctgggcctcaacgacatggcggccgagggcacctgggtggacatgaccggcgcccgcatcgcctacaagaactgggagactgagatcaccgcgcaacccgatggcggcaagaccgagaactgcgcggtcctgtcaggcgcggccaacggcaagtggttcgacaagcgctgccgcgatcagctgccctacatctgccagttcgggatcgtgtagccggc139 205259_atgcagactgggagttgctagcaaacaaatggcttacttacaaaagcagcttttagttcagacttagtttttataaaatgagaattctgacttacttaaccaggtttgggatggagatggtctgcatcagctttttgtattaacaaagttactggctctttgtgtgtctccaggtaactttgcttgattaaacagcaaagccatattctaaattcactgttgaatgcctgtcccagtccaaattgtctgtctgctcttatttttgtaccatattgctcttaaaaatcttggtttggtacagttcataattcaccaaaaagttcatataatttaaagaaacactaaattagtttaaaatgaagcaatttatatctttatgcaaaaacatatgtctgtctttgcaaagga140 205267_atgcacccagccttttaccatgtgggtttctttagtgtcttaaaagcgtccataagccaccattctgtggaaccaaggccccctccacgcaaacaccctccctcctggggacctctggagcctcagccagaagtaccattaggtttaattttaatttgttttgctggagaaacatcaggtttgtaggagactgagttgttagcaggtgtgcttagctcttgatagtgaacgtgtaccttgggaactggctcacccacctgctaatagcaccatcgtcactattaagcagacatttcagttggtagaatccatgtagaagtcatggacttttctgggaaatgacttttctgggaaatgacagtttctttgacatattttctttgcccactt 141205382_s_atcgccatcaccgagcgcttgatgtgcgcggagagcaatcgccgggacagctgcaagggtgactccgggggcccgctggtgtgcgggggcgtgctcgagggcgtggtcacctcgggctcgcgcgtttgcggcaaccgcaagaagcccgggatctacacccgcgtggcgagctatgcggcctggatcgacagcgtcctggcctagggtgccggggcctgaaggtcagggtcacccaagcaacaaagtcccgagcaatgaagtcatccactcctgcatctggttggtctttattgagcacctactatatgcagaaggggag 142 205403_atgggccacgccaggaatattcagaaaataatgagaactacattgaagtgccattgatttttgatcctgtcacaagagaggatttgcacatggattttaaatgtgttgtccataataccctgagttttcagacactacgcaccacagtcaaggaagcctcctccacgttctcctggggcattgtgctggccccactttcactggccttcttggttttggggggaatatggatgcacagacggtgcaaacacagaactggaaaagcagatggtctgactgtgctatggcctcatcatcaagactttcaatcctatcccaa143 205412_atgctgctctggttctcatgacggcagatgcagcgaagaggctcaatgttacaccactggcaagaatagtagcatttgctgacgctgctgtagaacctattgattttccaattgctcctgtatatgctgcatctatggttcttaaagatgtgggattgaaaaaagaagatattgcaatgtgggaagtaaatgaagcctttagtctggttgtactagcaaacattaaaatgttggagattgatccccaaaaagtgaatatcaatggaggagctgtttctctgggacatccaattgggatgtctggagccaggattgttggtcatttgactcatgccttgaagcaaggagaatacggtcttgccagtatttgcaatggaggaggaggtgcttctgccatgctaattcagaagctgtagacaacctctgctatttaaggagacaaccctatgtgaccagaa 144 205433_atggaaagcaggattccatcgctggaacaattacatgatggactggaaaaatcaatttaacgattacactagcaagaaagaaagttgtgtgggtctctaattaatagatttaccctttatagaacatattttcctttagatcaaggcaaaaatatcaggagcttttttacacacctactaaaaaagttattatgtagctgaaacaaaaatgccagaaggataatattgattcctcacatctttaacttagtattttacctagcatttcaaaacccaaatggctagaacatgtttaattaaatttcacaatataaagttctacagttaattatgtgcatattaaaacaatggcctggttcaatttctttctttccttaataaatttaagttttttccccccaaaattatcagtgctctgcttttagtcacgtgtattttcattaccactcgtaaaaaggtatcttttttaaatgaattaaatattgaaacactgtacaccatagtttaca 145205464_atgagggtgatgccatctaaccctgcccctgtccaccccgggtgggtgaaactcactgagcagccaagactgttgcccgaggactcactgtatggtgccctctccaaagggtcgggagggtagctctccaggccagagcttgtgtccttcaacagagaggccagcggcaactggtccgttactggccaagggctctgaagaatcaacggtgctggtacaggatacaggaataaattgtatcttcacctggttcctaccctcgtccctacctgtcctgatcctggtcctgaagacccctcggaacaccctctcctggtggcaggccacttccctcccagtgccagtctccatccaccccagagaggaacaggcgggtgggccatgtggttttctccttcctggccttggctggcctctggggcaggggtggtggagagatggaagggcatcaggtgtagggaccctgccaagtggcacctgatttactctag 146205480_s_atttaatgtgccaaggagccgttttctgcctgtcaaaaccacatcagatctcttgctggtgatgtcaaacctctatagtcttaatgcaggatctctgacaatgagtgaaaagcgggaatttcctacagtgcccttggttaaattaggcagttcttttacgaaggttcaagattatctaagaagatttgaaagtataccagatatgcttgaattggatcacctcacagtttcaggagatgtgacatttggaaaaaatgtttcattaaagggaacggttatcatcattgcaaatcatggtgacagaattgatatcccacctggagcagtattagagaacaagatagtgtctggaaaccttcgcatcttggaccactgaaatgaaaaatactgtggacacttaaataatgggctagtttcttacaatgaaatgttctctaggatttaggcactaaaaggtactttactatgttactgtaccctgc 147 205547_s_atcaagaatgatgggcactaccgtggagatcccaactggtttatgaagaaagcgcaggagcataagagggaattcacagagagccagctgcaggagggaaagcatgtcattggccttcagatgggcagcaacagaggggcctcccaggccggcatgacaggctacggacgacctcggcagatcatcagttagagcggagagggctagccctgagcccggcgctcccccagctccttggctgcagccatcccgcttagcctgcctcacccacacccgtgtggtaccttcagccctggccaagctttgaggctctgtcactgagcaatggtaactgcacctgggcagctcctccctgtgcccccagcctcagcccaacttcttacccgaaagcatcactgccttggcccctccctcccggcggcccccatcacctctactgtctcctccctgggctaagcaggggagaagcgggctgggggtagcctggatgtgggcgaagtccactgtcctccttggcggcaaaagcccatt 148 205554_s_attcaaagacttcgtgattatccccctgcacaccaccccagagacatccgttaaggagatcgatgagttggttgaggtctacacggacgtgaaacaccgctggaaggcggagaatttcattttcatgggtgacttcaatgccggctgcagctacgtccccaagaaggcctggaagaacatccgcttgaggactgaccccaggtttgtttggctgatcggggaccaagaggacaccacggtgaagaagagcaccaactgtgcatatgacaggattgtgcttagaggacaagaaatcgtcagttctgttgttcccaagtcaaacagtgtttttgacttccagaaagcttacaagctgactgaagaggaggccctggatgtcagcgaccactttccagttgaatttaaactacagtcttcaagggccttcaccaacagcaaaaaatctgtcactctaaggaagaaaacaaagagcaaacgctcctagacccaagggtctcatcttattaaccatttcttgcctctaaata149 205593_s_ataacgaggagcacatgaccctgctgaagatgattttgataaaatgctgtgatatctctaacgaggtccgtccaatggaagtcgcagagccttgggtggactgtttattagaggaatattttatgcagagcgaccgtgagaagtcagaaggccttcctgtggcaccgttcatggaccgagacaaagtgaccaaggccacagcccagattgggttcatcaagtttgtcctgatcccaatgtttgaaacagtgaccaagctcttccccatggttgaggagatcatgctgcagccactttgggaatcccgagatcgctacgaggagctgaagcggatagatgacgccatgaaagagttacagaagaagactgacagcttgacgtctggggccaccgagaagtccagagagagaagcagagatgtgaaaaacagtgaaggagactgtgcctgaggaaagcggggggcgtggctgcagttctggacgggctggccgagctgcgcgggatccttgtgcagggaagagctgccctgggcacctggcaccacaagaccatgttttctaa 150 205683_x_attgacgcaaaataccaccttggcgcctacacgggagacgacgtccgcatcgtccgtgacgacatgctgtgtgccgggaacacccggagggactcatgccagggcgactccggagggcccctggtgtgcaaggtgaatggcacctggctgcaggcgggcgtggtcagctggggcgagggctgtgcccagcccaaccggcctggcctggcatctacacccgtgtcacctactacttggactggatccaccactatgtccccaaaaagccgtgagtcaggcctgggttggccacctgggtcactggaggaccaacccctgctgtccaaaacaccactgcttcctacccaggtggcgactgccccccacaccttccctgccccgtcctgagtgccccttcctgtcctaagccccctgctctcttctgagccccttcccctgtcctgaggacccttccctatcctgagcccccttccctgtcctaagcctgacgcctgcaccgggccctccagccctcccctgcccagatagctggtggtgggcgctaatcct 151 205892_s_atgaagagggagctctattgccaccatgagtttctccggcaagtaccaactgcagagccaggaaaactttgaagccttcatgaaggcaatcggtctgccggaagagctcatccagaaggggaaggatatcaagggggtgtcggaaatcgtgcagaatgggaagcacttcaagttcaccatcaccgctgggtccaaagtgatccaaaacgaattcacggtggg 152 205929_atccttctctggtctccttgagatgatcgtagacacagggatgattcccacccaaacccacgtattcattcagtgagttaaacacgaattgatttaaagtgaacacacacaagggagcttgcttgcagatggtctgagttcttgtgtcctggtaattcctctccaggccagaataattggcatgtctcctcaacccacatggggttcctggttgttcctgcatcccgatacctcagccctggccctgcccagcccatttgggctctggttttctggtggggctgtcctgctgccctcccacagcctccttctgtttgtcgagcatttcttctactcttgagagctcaggcagcgttagggctgcttaggtctcatggaccagtggctggtctcacccaactgcagtttactattgctatcttttctggatgatcagaaaaataattccataaatctattgtctacttgcgattttttaaaaaatgtatatttttatatatattgttaaatcctttgcttcattcca153 205935_attctcccaacctctactgtaaactttctggtccgagaacgagccgaacacagcgcgacgcagggactaggacggcccggtgaccgcgcggattcaggattgcggggacgcagaaaggttaaggcacttttaaaaactatagcaaggctcctgtttatttattctactttctttccctaataatcaaaacaccgcgtaggctcctccgtttatcagtattaatggtgtaactttgttggcaatatttgccgtgtagaattttttttagatatccattgtaaatttgaaacaaagaccgatctgtgtaaaaacaaatttccatatgttttatataaatatatatataatatgaaggactaccctcctttttttttttttgtattttggctgctagagtgcagcatttgtgacacgtatttgaaatttgaaatttccttctgcactgtataaaaggaccatttgaggatgttttgccttttgtgtatttt 154 205950_s_atgagccccattcacaaattttgacccctctactctccttccttcatccctggatttctggacctaccctggctctctgactcatcctcctttatgagagtgtaacttggatcatctgtaaggagagcatcagtgtcagctcagagcagctggcacaattccgcagccttctatcaaatgttgaaggtgataacgctgtccccatgcagcacaacaaccgcccaacccaacctctgaagggcagaacagtgagagcttcattttgatgattctgagaagaaacttgtccttcctcaagaacacagccctgcttctgacataatccagttaaaataataatttttaagaaataaatttatttcaatattagcaagacagcatgccttcaaatcaatctgtaaaactaagaaacttaaattttagttcttactgcttaattcaaataataattagtaagctagcaaatagtaatctgtaagcataagcttatcttaaattcaagtttagtttgaggaattctttaaaattacaactaagtgatttgtatgtctatttttttc 155 206000_atggcagcttttttatcagccttgctttggataggacctccaaggactaagcctccagccccatgtgtgacccttgtcatctctctgccccacataattatgttactttgctatgtgctcctaatgtatctagtgtgtcctgtgacaacactcatcacacttcattgtaaatcacttgttttattgactgtctttcctatagactgtaagctccatgagggcaggcacatgttgttctcattgaccgtgctggccccagtgcctagatgcatggctggcacattgttggcactcaacaatggttgaatgaataaaacaataaatgaatgaataactaagatatagaaactctcatttatattgcagattgaatatatatgatgaaattcttatgttgaatatgttagaatcaaatactcatttttcattagatacagtagtgtcatcactcttttaagatcttgttaaagatttcaaataaaggtacttctggcgagccaggctgcacagcatttgctttcct156 206094_x_attatttgaatatgtatcgtgccccctccggagtctttgatcaggatgacatgtgccatttttcagaggacgtgcagacaggctggcattctagattacttttcttactctgaaacatggcctgtttgggagtgcgggattcaaaggtggtcccacggctgcccctactgcaaatggcagttttaatcttatcttttggcttctgcagatggttgcattgatccttaaccaataatggtcagtcctcatctctgtcctgacttcataggt 157 206134_atctttctatattgttatcagtccaggaaacaggtaaacagatgtaattagagacattggctctttgtttaggcctaatctttctttttacttttttttttcttttttctttttttttaaagatcatgaatttgtgacttagttctgccctttggagaacaaaagaaagcagtcttccatcaaatcaccttaaaatgcacggctaaactattcagagttaacactccagaattgttaaattacaagtactatgctttaatgcttctttcatcttactagtatggcctataaaaaaaataataccacttgatgggtgaaggctttggcaatagaaagaagaatagaattcaggttttatgttattcctctgtgttcacttcgccttgctcttgaaagtgcagtatttttctacatcatgtcgagaatgattcaatgtaaatatttttcattttatcatgtatatcctatacacacatctccttcatcatcatatatgaagtttattttgagaagtctacattgcttacattt158 206143_attaacaatccatgatgctgttttgcatattttgatgaagaaagattacagtacttcaaagtttaatcccagtcaggaaaaagatggaaaaattgattttaccataaatacaaatggaggattacgtaatcgggtatatgaggtgccagttgaaacaaaattctaatcaacatataattcagaaggatcttcatctgactatgacataaaaacaactttatacccagaaagttattgataagttcatacattgtacgaagagtatttttgacagaatatgtttcaaactttggaacaagatggttctagcatggcatatttttcacatatctagtatgaaattatataagtattctaaattttatatcttgtagctttatcaaagggtgaaaattattttgttcatacatatttttgtagcactgacagatttccatcctagtcactaccttcatgcataggtttagcagtatagtggcgccactgttttgaatct 159 206149_attcatcaggctccagttattctccatctcccagctcagctttttctgtctgtaagcctgattttcaggaaggctctttcctagtgatggagatgaccaccatcagctccaggcttctatcctgctaacccagtaacccagtgggaagagatttacttattccaataattccaagtggagagtgtcattgacccgtttggggtctcatctctacttctaggggaatgaaacactttgagtggccaggcctgtgtcatgtgctaattcctagagccagggaaataaggtctgaggattcaggatggggtgaaaggtggttgcttaaaggaaaatgaaatacaattagcagaataaggggaaacgagtggtctgctctgctcgggcaaaacaagagatgcccattactgtgagggacccttgaagtctggactcttaaatgggtttttgctgatttcctgggtgcatgctagg 160 206198_s_ataccagcaacaacttcaatccggtggagaacaaagatattgtggttttaacctgtcaacctgagactcagaacacaacctacctgtggtgggtaaacaatcagagcctcctggtcagtcccaggctgctgctctccactgacaacaggaccctcgttctactcagcgccacaaagaatgacataggaccctatgaatgtgaaatacagaacccagtgggtgccagccgcagtgacccagtcaccctgaatgtccgctatgagtcagtaca 161206199_atatattagttaccctggtgtgctgtattctctaaaacctttaaatgtttgcatgcagccattcgtcaaatgtcaaatattctctctttggctggaatgacaaaaactcaaataaatgtatgattaggaggacatcataacctatgaatgatggaagtccaaaatgatggtaactgacagtagtgttaatgccttatgtttagtcaaactctcatttaggtgacagcctggtgactccagaatggagccagtcatgctaaatgccatatactcacactgaaacatgaggaagcaggtagatcccagaacagacaaaactttcctaaaaacatgagagtccaggctgtctgagtcagcacagtaagaaagtcctttctgctttaactcttagaaaaaagtaatatgaagtattctgaaattaaccaatcagtttatttaaatcaatttatttatattcttctgttcctggattcccattttacaaaacccactgttctactgttgtattgcccagt162 206208_atcccaggaccctgaagacgaaattgcggtgctggcctttctggtggaggctggaacccaggtgaacgagggcttccagccactggtggaggcactgtctaatatccccaaacctgagatgagcactacgatggcagagagcagcctgttggacctgctccccaaggaggagaaactgaggcactacttccgctacctgggctcactcaccacaccgacctgcgatgagaaggtcgtctggactgtgttccgggagcccattcagcttcacagagaacagatcctggcattctctcagaagctgtactacgacaaggaacagacagtgagcatgaaggacaatgtcaggcccctgca 163 206209_s_ataccacaccgacctgcgatgagaaggtcgtctggactgtgttccgggagcccattcagcttcacagagaacagatcctggcattctctcagaagctgtactacgacaaggaacagacagtgagcatgaaggacaatgtcaggcccctgcagcagctggggcagcgcacggtgataaagtccggggccccgggtcggccgctgccctgggccctgcctgccctgctgggccccatgctggcctgcctgctggccggcttcctgcgatgatggctcacttctgcac164 206262_atactgactggacgcacgtggaaaggagctatttttggaggctttaagagtaaagaatctgtcccgaaacttgtggctgactttatggctaagaagttttcactggatgcattaataacaaatattttaccttttgaaaaaataaatgaaggatttgacctgcttcgctctggaaagagtatccgtaccgtcctgacgttttgaaacaatacagatgccttcccttgtagcagttttcagcctcctctaccctacatgatctggagcaacagctaggaaatatcattaattctgctcttcagagatgttaaaaataaattacacgtgggagctttccaa 165 206377_atgttggtcactgttatttgcctactgctggaagaaggacaaccgctggcaaggtagcgttccccaatctgaatacctgcaggctcccacatgagggagagggcagactcaggtgggaagatgtgccatgcgtaaggcatcaacgtgtatctgtgggatcttcgttgccttcagtaatcagggtgtgaaaaaagcagacaagttgtgtgtgtgtgtgtgtgtctaagaaaacttgtgtgcttttcaaaaaggcagtgctaagcacaagatttcaagaaagcctcttcttgttgcctagctgagtgggagagtcattttccccagacactacatttggatacaggtgccaaagaacattattaaggaattatttagaaacaatgtgtctagtttaagaaagtggttttcagtattgtgacaatacaacgtttttacaaggttgttttctaccaccatattttaaagatatttttatgaccgtgtatactcacactttgctt 166206385_s_ataaagcccttcatctaatatttgttgctattgccaatttttcaatgaaatgacctaaaaacaacaaaaaaaaataacctatacggtagttgctttagggggtggggggatgctatctgttagtgcttaaaagggggtaaatgcttgccgctttagaggtggatggtgctcataaaaggccccagtcgggggtatttaaaaaggactgaacagaaatccttagctagtagaatggcagcacgctgtaaaattattactgtattgtgtactggctataagatgtagacacctttcagtaagccaatcatttgtaaccattctagcagtgtcatattaggttaataaggctgctgtgttttaaagggcatttttatttgggttttggtgaaattctttaatttgttgattatattcacataaaatcagcattcattgacacatagctctaatgacatatgtatgaaaaaccatacactggatgacctagtcga 167 206422_atctgatggttctttctctgatgagatgaacaccattcttgataatcttgccgccagggactttataaactggttgattcagaccaaaatcactgacaggaaataactatatcactattcaagatcatcttcacaacatcacctgctagccacgtgggatgtttgaaatgttaagtcctgtaaatttaagaggtgtattctgaggccacattgctttgcatgccaataaataaattttcttttagtgttgtgtagccaaaaattacaaatggaataaagttttatcaaaatattgctaaaatatcagctttaaaatatgaaagtgctagattctgttattttcttcttattttggatgaagtaccccaacctgtttacatttagcgataaaattatttttctatgatataatttgtaaatgtaaattattccgatctgacatatctgcattataataataggagaatagaagaactggtagccacagtggtgaaattggaaagagaactttcttcctgaaacctttgtcttaaaaatactcagctttcaatgtatcaa168 206461_x_atgccggctcctgcaagtgcaaaaagtgcaaatgcacctcctgcaagaagagctgctgctcctgttgccccctgggctgtgccaagtgtgcccagggctgcatctgcaaaggggcgtcagagaagtgcagctgctgtgcctgatgtcgggacagccctgctgtcagatgaaaacagaatgacacgtaaaatccgaggttttttttttctacaactccgactcatttgctacattcctttttttctg 169 206561_s_atttccctgctggaggatcccaagattaaggagattgctgcaaagcacaaaaaaaccgcagcccaggttctgatccgtttccatatccagaggaatgtgattgtcatccccaagtctgtgacaccagcacgcattgttgagaacattcaggtctttgactttaaattgagtgatgaggagatggcaaccatactcagcttcaacagaaactggagggcctgtaacgtgttgcaatcctctcatttggaagactatcccttcaatgcagaatattgaggttgaatctcctggtgagattatacaggagattctctttcttcgctgaagtgtgactacctccactcatgtcccattttagccaagcttatttaagatcacagtgaacttagtcctgttatagacgagaatcgaggtgctgttttagacatttatttctgtatgttcaactaggatcagaatatcacagaaaagcatggcttgaataaggaaatgacaattttttccacttatctgatcagaacaaatgtttattaagcatcagaaactctgccaacactga 170 206576_s_attaagtccagtagtagcaaagccccaaatcaaagccagcaagaccacagtcacaggagataaggactctgtgaacctgacctgctccacaaatgacactggaatctccatccgttggttcttcaaaaaccagagtctcccgtcctcggagaggatgaagctgtcccagggcaacaccaccctcagcataaaccctgtcaagagggaggatgctgggacgtattggtgtgaggtcttcaacccaatcagtaagaaccaaagcgaccccat 171206637_attgagcctggggttctggtgttagaatatttttaagtaggctttactgagagaaactaaatattggcatacgttatcagcaacttcccctgttcaatagtatgggaaaaataagatgactgggaaaaagacacacccacaccgtagaacatatattaatctactggcgaatgggaaaggagaccattttcttagaaagcaaataaacttgatttttttaaatctaaaatttacattaatgagtgcaaaataacacataaaatgaaaattcacacatcacatttttctggaaaacagacggattttacttctggagacatggcatacggttactgacttatgagctaccaaaactaaattctttctctgctattaactggctagaagacattcatctatttttcaaatgttctttcaaaacatttttataagtaatgtttgtatctatttcatgctttact 172 206641_atatttctttggcagttttcgtgctaatgtttttgctaaggaagataagctctgaaccattaaaggacgagtttaaaaacacaggatcaggtctcctgggcatggctaacattgacctggaaaagagcaggactggtgatgaaattattcttccgagaggcctcgagtacacggtggaagaatgcacctgtgaagactgcatcaagagcaaaccgaaggtcgactctgaccattgctttccactcccagctatggaggaaggcgcaaccattcttgtcaccacgaaaacgaatgactattgcaagagcctgccagctgctttgagtgctacggagatagagaaatcaatttctgctaggtaattaaccatttcgactcgagcagtgccactttaaaaatcttttgtcagaatagatgatgtgtcagatctctttaggatgactgtatttttcagttgccgatacagctttttgtcctctaactg 173 206664_atgaagacactaccaacatgatattacgtattgatctgaccacacacaatgttactctagaagaaccaatagaaatcaactggtcatgaagatcaccatcaattttagttgtcaatgggaaaaaacaccaggatttaagtttcacagcacttacaattttccctcttcacttggttcttgtactctacaaaatatagctttcataacatcgaaaagttattttgtagcgtacatcaatgataatgctaattttattatagtaatgtgacttggattcaattttaaggcatatttaacaaaatttgaatagccctatttatccttgttaagtatcagctacaattgtaaactagttactaaacatgtatgtaaatagctaagatataatttaaacgtgatttttaaattaaataaaatttttatgtaattatatatactatatttttctcaatgtttagcagatttaagatatgtaacaacaattatttgaagatttaattacttcttagtatgtgcattta174 206710_s_atattgcaatttcttaggtaaccttatatttacaataaatgaagattaccctcaaatgctagaagctgtctaggtccgtccggtgtgtcagatttcctcagattagatgtgccaataaccaagtttattcagtaaacaacttgtacttgtttcatctggtttattactctcacccataaacagtaatgactctctgaccctctggaaatatgtaatgcttccaatcttg 175 206784_atttttggacctgcggtggtggccaaccactggaacttccactggatctactggctgggcccactcctggctggcctgcttgttggactgctcattaggtgcttcattggagatgggaagacccgcctcatcctgaaggctcggtgagcagagctcgtgggattcctgctgctccaggtgtcctcagctcacctgtcccagactgaggacaggggagttcctgcatttcctgccagggcagaggcccagaggagcgaccccctgcttccactgcttgggcctgctttctcagatagactgactgctgaggaggctctaggttcttggaattcctttgtgctcatcagagaccccagcctggggaacacgctgcccgcactgcccagagagcagtgcaaacaccacaacacgagcgtgtttcttgagaggaatgtccccgagttggacaaggaggctgtttctgcacatcagctcatttcc 176 207003_atgaggggtcaccgtgcaggatggaaatttctccttttctctggagtcagtgaagaagctcaaagacctccaggagccccaggagcccagggttgggaaactcaggaactttgcacccatccctggtgaacctgtggttcccatcctctgtagcaacccgaactttccagaagaactcaagcctctctgcaaggagcccaatgcccaggagatacttcagaggctggaggaaatcgctgaggacccgggcacatgtgaaatctgtgcctacgctgcctgtaccggatgctaggggggcttgcccactgcctgcctcccctccgcagcagggaagctcttttctcctgcagaaagggccacccatgatactccactcccagcagctcaacctaccctggtccagtcgggaggagcagcccggggaggaactgggtgact 177 207080_s_attcgtctgcttcacaagctatcgctatggtgttcgtgcgcaggccgtggcccgccttgaccacagtgcttctggccctgctcgtctgcctaggggcgctggtcgacgcctaccccatcaaacccgaggctcccggcgaagacgcctcgccggaggagctgaaccgctactacgcctccctgcgccactacctcaacctggtcacccggcagcggtatgggaaaagagacggcccg 178 207126_x_attatttgaatatgtatcgtgccccctccggtgtctttgatcaggatgacatgtgccatttttcagaggacgtgcagacaggctggcattctagattacttttcttactctgaaacatggcctgtttgggagtgcgggattcaaaggtggtcccaccgctgcccctactgcaaatggcagttttaatcttatcttttggcttctgcagatggttgcaattgatccttaaccaataatggtcagtcctcatctctgtcctgcttcataggtgccaccttgtgtgtttaaa 179207134_x_attgacgcaaaataccaccttggcgcctacacgggagacgacgtccgcatcgtccgtgacgacatgctgtgtgccgggaacacccggagggactcatgccagggcgactccggagggcccctggtgtgcaaggtgaatggcacctggctgcaggcgggcgtggtcagctggggcgagggctgtgcccagcccaaccggcctggcatctacacccgtgtcacctactacttggactggatccaccactatgtccccaaaaagccgtgagtcaggcctgggttggccacctgggtcactggaggaccaacccctgctgtccaaaacaccactgcttcctacccaggtggcgactgccccccacaccttccctgccccgtcctgagtgccccttcctgtcctaagccccctgctctcttctgagccccttcccctgtcctgaggacccttccccatcctgagcccccttccctgtcctaagcctgacgcctgcaccgggccctccggccctcccctgcccaggcagctggtggtgggcgct 180 207245_atatgatcacaaaatgttgcctgttttgtttccgaaagcttgccaaaacaggaaagaagaagaaaagggattagttatatcaaaagcctgaagtggaatgaccaaaagatgggactcctcctttattccagcatggagggttttaaatggaggatttcctttttcctgcgacaaaacgtcttttcacaacttaccctgttaagtcaaaatttattttccaggaatttaatatgtactttagttggaattattctatgtcaatgatttttaagctatgaaaaataataatataaaaccttatgggcttatattgaaatttattattctaatccaaaagttaccccacacaaaagttactgagcttccttatgtttcacacattgtatttgaacacaaaacattaacaactccactcatagtatcaacattgttttgcaaatactcagaatattttggcttcattttgagcagaat 181 207266_x_atcaagtatcggggctctgctatcaaggtgcaaagtccttcgtggatgcaacctcaaccatatattctacagcaccctggtgccgtgttaactccctcaatggagcacaccatgtcactacagcccgcatcaatgatcagccctctggcccagcagatgagtcatctgtcactaggcagcaccggaacatacatgcctgcaacgtcagctatgcaaggagcctacttgccacagtatgcacatatgcagacgacagcggttcctgttgaggaggcaagtggtcaacagcaggtggctgtcgagacgtctaatgaccattctccatatacctttcaa 182 207390_s_attggactggtgtcgagccaagactcggggcctacgagcacgtcgacatccagaacttctcctccagctggagtgatgggatggccttctgtgccctggtgcacaacttcttccctgaggccttcgactatgggcagcttagccctcagaaccgacgccagaacttcgaggtggccttctcatctgcggagatgctggtggactatgtgcccctggtggaggtggacgacatgatgatcatgggcaagaagcctgaccccaagtgtgtcttcacctatgtgcagtcgctctacaaccacctgcgacgccacgaactggcctcgcgcggcaagaatgtctagcctgcccgcccgcatggccagccagtggcaactgccgcccccactctccgggcaccgtctcctgcctgtgcgtccgcccaccgctgccctgtctgttgcgacaccctcccccccacatacacacgcagcgttttga 183207392_x_atggatgtgatagcattcctgctggcctgcgtggcaactgtgatatttatcatcacaaaattttgcctgttttgtttccgaaagcttgccaaaacaggaaagaagaagaaaagagattagttatatcaaaagcctgaagtggaatgactgaaagatgggactcctcctttatttcagcatggagggttttaaatggaggatttcctttttcctgtgacaaaacatcttttcacaacttaccttgttaagacaaaatttattttccagggatttaatacgtactttagttggaattattctatgtcaatgatttttaagctatgaaaaatacaatggggggaaggatagcatttggagatatacctaatgttaaatgacgagttactggatgcagcacgcaacatggcacatgtgtatacatatgtagctaacccttcgttgtgcacatgtaccctaaaacttaaagtataatttaaaaaaagcaaaaaaaaaaaataccaactcttttttttaaaccaggaaggaaaatgtgaacatggaaacaacttctagtattggatctg 184 207432_atgccccggagtgcagctgcggggacccgctgctcgaccccggcctgccggagcccgaggccccgccccctgcgggtcccgaaccgcttaccctcatccctgggcctgtcgagcccttcagcatcgtgaccatgcccgggccccggggtccggcgccaccctggctgcccagccctattggcgaggaggaggagaatctggcctgagatcttagagcccagccccctaaggacagggaaccaggtccctgcacggcacccacgcaggtgtcccggtctgcataagcctcgtatgcctttgtaaagtccacctacacttttgaccagctctcgctgcccgcatgtgtttggcgctgtgctaggggcgggagttcttccagactcttggaccagcccgccctgaccaccagctctacttcccaacccccactgcctgagaggtctctatcagtgtcctgcctgaattctttccttcaagtgaagatgtgactgactacctcctcgagttgtcatga185 207502_atgaacccagggagcgcgatgggctgcagggctgcgtcagggctcctgccaggagtggccgtggtcctcctgctgctgctgcagagcacacagtcagtctacatccagtaccaaggcttccgggtccagctggaatccatgaagaagctgagtgacctggaggcacagtgggcacccagcccccgcctgcaggcccagagcctcctgcccgccgtgtgccaccaccctgctctgcctcaggaccttcagcctgtctgcgcctcgcaggaggcttccagcatcttcaagaccctgaggaccatcgctaacgacgactgtgagctgtgtgtgaacgttgcgtgtaccggctgcctctgagatagccctgggtaccctgagcccaccagggacacctcgcccttcagcccaccaccctggcaggcttccatccccgtccatgctcaagatgggtc 186 207761_s_atttattcttagcgtcactggtctggctttcagaattaacatacaaggttgccacacctagttctgcccagctttatgtcttttattccagtattccaccaaagtttgttttcctgcattccagttctcaagtcttaagataaagattgtacttgacagtttagtatatccataaaactatttgaggtggttaaggttcttgggttcattttccttaatactttgctgaatattgtagattgtaggcaatgaaaaagtctactaaattaggaaaaccttgaataattaggtatcctaggtaagagcccctaaacatcaagcaatctgtgagtctgtaaagaaataaatattttttggattattcttatctaattccacccctgttggaagatgatttctttgttctttgcaactatggaagctgtgaaaatcatcacaagtgcctctgaaagcgagtgttaggttggttagagggt 187 207961_x_atgtgacggtgctgaagaaggccctggatgaagagacgcggtcccatgaggctcaggtccaggagatgaggcagaaacacgcacaggcggtggaggagctcacagagcagcttgagcagttcaagagggccaaggcgaacctagacaagaataagcagacgctggagaaagagaacgcagacctggccggggagctgcgggtcctgggccaggccaagcaggaggtggaacataagaagaagaagctggaggcgcaggtgcagacactgagtttttagaaaaacatatccacggtaaccggtccctggcaattctgtttacatgaaatggggagaaagtcaccgaaatgggtgccgccggcccccactcccaattcattccctaacctgcaaacctttccaacttctcacgtcaggcctttgagaattctttccccctctcctggtttccacacctcagacacgcacagttcaccaagtgccttctgtagtcacatgaattgaaaaggagacgctgctcccacggaggggagcaggaatgctgcactgtttacaccctgactgtgcttaaa 188207977_s_attagtggccgtgaggagcatcttcagtaagaaggaaggttctgacagacaatggaactacgcctgcatgcccacgccacagagcctcggggaacccacggagtgctggtgggaggagatcaacagggctggcatggaatggtaccagacgtgctccaacaatgggctggtggcaggattccagagccgctacttcgagtcagtgctggatcgggagtggcagttttactgttgtcgctacagcaagaggtgcccatattcctgctggctaacaacagaatatccaggtcactatggtgaggaaatggacatgatttcctacaattatgattactatatccgaggagcaacaaccactttctctgcagtggaaagggatcgccagtggaagttcataatgtgccggatgactgaatacgactgt 189 207980_s_ataatgtcatagacactgatttcatcgacgaggaagttcttatgtccttggtgatagaaatgggtttggaccgcatcaaggagctgcccgaactctggctggggcaaaacgagtttgattttatgacggacttcgtgtgcaaacagcagcccagcagagtgagctgttgactcgatcgaaacccc190 208131_s_atccccccaattgctgccaatagtggataacatgtatcactcactgccaaaaatagaaagtgaccatgaaaaataaattcgctggggaagggggctccatgctggtgtggccaaggctgagagctctctcttctctgttacaaaacgagataagcaagtnttagaattgccttaaggccacactggcatctccctgaccttctccagggacagaagcaggagtaagtttctcatcccatgggcgaccagggccatctcctcccaccagtggcccccactcacagggagctggcaatgccctacctgcctgttctccagatggagaaacaggctctgagatttcacaggtcttgcccaaagtcattgattttaatgattaaaaagaataaacacagtgtttcctgagtagcagtgattgttatgccttgctatttta 191 208370_s_atgatgtattaacctacctgtgaatcatatgttgtaggaaaagctgttcccatgtctaacaggacttgaattcaaagcatgtcaagtggatagtagatctgtggcgatatgagagggatgcagtgcctttccccattcattcctgatggaattgttatactaggttaacatttgtaatttttttctagttgtaatgtgtatgtctggtaaataggtattatattttggccttacaataccgtaacaatgtttgtcattttgaaatacttaatgccaagtaacaatgcatgctttggaaatttggaagatggttttattctttgagaagcaaatatgtttgcattaaatgctttgattgttcatatcaagaaattgattgaacgttctcaaaccctgtttacggtacttggtaagagggagccggtttgggagagaccattgcatcgctgtccaagtgtttcttgt 192 208383_s_atagggcaagtgttcccaaattgacgccacctaataatcatcaccacaccgggagcagatctgaaggcacactttgatttttttaaggataagaaccacagaacactgggtagtagctaatgaaattgagaagggaaatcttagcatgcctccaaaaattcacatccaatgcatactttgttcaaatttaaggttactcaggcattgatcttttcagtgttttttcacttagctatgtggattagctagaatgcacaccaaaaagatacttgagctgtatatatatatgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgcatgtatgtgcacatgtgtctgtgtgatatttggtatgtgtatttgtatgtactgttattcaaaatatatttaatacctttggaaaatcttgggcaagatgacctactagttttccttgaaaaaaagttgctttgttattaatattgtgct 193 208399_s_atccgagccgagcttactgtgagtgtggagatgttatcccaccatgtaaagtcgcctgcgcaggggagggctgcccatctccccaacccagtcacagagagataggaaacggcatttgagtgggtgtccagggccccgtagagagacatttaagatggtgtatgacagagcattggccttgaccaaatgttaaatcctctgtgtgtatttcataagttattacaggtataaaagtgatgacctatcatgaggaaatgaaagtggctgatttgctggtaggattttgtacagtttagagaagcgattatttattgtgaaactgttctccactccaactcctttatgtggatctgttcaaagtagtcactgtatatacgtatagagaggtagataggtaggtagattttaaattgcattctgaatacaaactcatactccttagagcttgaattacatttttaaaatgcatatgtgctgtttggcaccgtggcaagatggtatcagagagaaacccatcaattgctcaaatactc194 208450_atggagctgtcaccatgacgggggaacttgaggttaagaacatggacatgaagccggggtcaaccctgaagatcacaggcagcatcgccgatggcactgatggctttgtaattaatctgggccaggggacagacaagctgaacctgcatttcaaccctcgcttcagcgaatccaccattgtctgcaactcattggacggcagcaactgggggcaagaacaacgggaagatcacctgtgcttcagcccagggtcagaggtcaagttcacagtgacctttgagagtgacaaattcaaggtgaagctgccagatgggcacgagctgacttttcccaacaggctgggtcacagccacctgagctacctgagcgtaaggggcgggttcaacatgtcctc195 208581_x_atgcgtgttttcctcttgatcgggaactcctgcttctccttgcctcgaaatggaccccaactgctcctgctcgcctgttggctcctgtgcctgtgccggctcctgcaaatgcaaagagtgcaaatgcacctcctgcaagaagagctgctgctcctgctgccctgtcggctgtgccaagtgtgcccagggctgcatctgcaaagggacgtcagacaagtgcagctgctgtgcctga 196 208596_s_atcccgaccatcgaatcttgcgaacaacacgatacttgttaagtggctaccccaaaacgatctgcttggtcacccgatgacccgtgcctttatcacccatgctggttcccatggtgtttatgaaagcatatgcaatggcgttcccatggtgatgatgcccttgtttggtgatcagatggacaatgcaaagcgcatggagactaagggagctggagtgaccctgaatgttctggaaatgacttctgaagatttagaaaatgctctaaaagcagtcatcaatgacaaaagttacaaggagaacatcatgcgcctctccagccttcacaaggaccgcccggtggagccgctggacctggccgtgttctgggtggagtttgtgatgaggcacaagggcgcgccacacctgcgccccgcagcccacgacctcacctggtaccagtaccattccttggacgtgattggtttcctcttggccgtcgtgctgacagtggccttcatcacctttaaatgttgtgcttatggctaccggaaatgcttggggaaaaaagggcgagttaagaaagcccacaaatccaagacc 197 208747_s_attgcagaggcctatgttttcactcctaacatgatctgtgctggaggagagaagggcatggatagctgtaaaggggacagtggtggggcctttgctgtacaggatcccaatgacaagaccaaattctacgcagctggcctggtgtcctgggggccccagtgtgggacctatgggctctacacacgggtaaagaactatgttgactggataatgaagactatgcaggaaaatagcaccccccgtgaggactaatccagatacatcccaccagcctctccaagggtggtgaccaatgcattaccttctgttccttatgatattctcattatttcatcatgactgaaagaagacacgagcgaatgatttaaatagaacttgattgttgagacgccttgctagaggtagagtttgatcatagaattgtgctggtcatacatttgtggtctgactccttggggtcctttccccggagtacctattgtagataacactatgggtggggcactccttt198 208763_s_atgggcctaaccagccttgggagtattgactggtcccttacctcttatggctaagtctttgactgtgttcatttaccaagttgacccagtttgtcttttaggttaagtaagactcgagagtaaaggcaaggaggggggccagcctctgaatgcggccacggatgccttgctgctgcaaccctttccccagctgtccactgaaacgtgaagtcctgttttgaatgccaaacccaccattcactggtgctgactacatagaatggggttgagagaagatcagtttgggcttcacagtgtcatttgaaaacgttttttgttttgttttgtaattattgtggaaaactttcaagtgaacagaaggatggtgtcctactgtggatgagggatgaacaaggggatggctttgatccaatggagcctgggaggtgtgcccagaaagcttgtctgtagcgggttttgtgagagtgaacactttccactttttgacaccttatcctgatgtatggttc199 208788_atagatgtgtttagaacctcttgtttaaaaataatagactgcttatcataaaatcacatctcacacatttgaggcagtggtcaaacaggtaaagcctatgatgtgtgtcattttaaagtgtcggaatttagcctctgaataccttctccattgggggaaagatattcttggaaccactcatgacatatcttagaaggtcattgacaatgtataaactaattgttggtttgatatttatgtaaatatcagtttaccatgctttaattttgcacattcgtactatagggagcctattggttctctattagtcttgtgggttttctgtttgaaaaggagtcatggcatctgtttacatttaccttatcaaacctagaatgtgtatatttataaatgtatgtcttcattgctaggtactaatttgcagatgtctttacatatttcaatacagaaactataacattcaatagtgtgctgtcaaagtgtgcttagctcacctggatatacctacattg 200 208789_atgaagggagtgttgctcccagtccagaggcctgattctgttcggactgggttctcaagacacgaccaggttctcaagacacgagtccccttgttcctccccattaaagggggtttgtcagaagcaagaacagcccctctccccagtcacagcctgaagggaggccccgagagcttcctccttccccccacctgctccttaccttctctgccctgctttttagaactgcagttcattgttttaagggattgggggagggagcctggggacacaaaccttttatacaatacaaagctttgctttttttttttttttnnnnnnnccttttccctttctcggttctcttctctcctctgaatggctgaagacccctctgccgagggaggttggggattgtgggacaaggtcccttggtgctgatggcctgaaggggcctgagctgtgggcagatgcagttttctgtgggcttggggaacctctcacgttgctgtgtcctggtgagcagcccgaccaataaacctgcttt201 208791_atggctgcctgcggatgaaggaccagtgtgacaagtgccgggagatcttgtctgtggactgttccaccaacaacccctcccaggctaagctgcggcgggagctcgacgaatccctccaggtcgctgagaggttgaccaggaaatataacgagctgctaaagtcctaccagtggaagatgctcaacacctcctccttgctggagcagctgaacgagcagtttaactgggtgtcccggctggcaaacctcacgcaaggcgaagaccagtactatctgcgggtcaccacggtggcttcccacacttctgactcggacgttccttccggtgtcactgaggtggtcgtgaagctctttgactctgatcccatcactgtgacggtccctgtagaagtctccaggaagaacccta202 208792_s_atagcagctgaacgagcagtttaactgggtgtcccggctggcaaacctcacgcaaggcgaagaccagtactatctgcgggtcaccacggtggcttcccacacttctgactcggacgttccttccggtgtcactgaggtggtcgtgaagctctttgactctgatcccatcactgtgacggtccctgtagaagtctccaggaagaaccctaaatttatggagaccgtggcggagaaagcgctgcaggaataccgcaaaaagcaccgggaggagtgagatgtggatgttgc203 208894_atcgatcaccaatgtacctccagaggtaactgtgctcacgaacagccctgtggaactgagagagcccaacgtcctcatctgtttcatagacaagttcacccca204 208920_atgatataccatgtattcacactttaaaaaatacacatagcagagtatcggaaagtatgtaccaaaacattgatctggctaccactgggagtcaggatcatgagttcatcttcttcntncttnnnactgcttttccaaacattctccagtaagcaggtactacatttataatggaaggaattttttaaaaaattttaagctgtacactttcaagtaagatctgaattctaatgctggcttgtgcctcttactatgtggtttggtcattatagataatgcccagtttcagtttccccatctttgaaaaggagataatatgttatctcttgggagtagttctgaatatgaagtgtgttgatacaagaagcactgacaatgtttctgtttcttaaatttaaaactggcctggtttgccttttttatcaagagagcttaacagataaaaaatgaaattagtctattttctacttgccagcagagtatctgtcttattttaggatgcagtgtgaaacttaccattcaactgaacaac205 209047_atgaaggctggattctatctacataagtcctttcaattccaccagggccagagcagctccaccactgtgcacttagccatgatggcaacagaaaccaagagacacaattacgcaggtatttagaagcagagggacaaccagaaggcccttaactatcaccagtgcatcacatctgcacactctcttctccattccctagcaggaacttctagctcatttaacagataaagaaactgaggcccacggtttcagctagacaatgatttggccaggcctagtaaccaaggccctgtctctggctactccctggaccacgaggctgattcctctcatttccagcttctcagtttctgcctgggcaatggccaggggccaggagtggggagagttgtgatggaggggagaggggtcacacccaccccctgcctggttntaggctgctgcacaccaaggccctgcatctgtctgctctgcatatatgt 206209074_s_atagacagctgtttagggtcttctcccctcacccatgctttcatcatcccctccgcacagcctccccgtccaggccttctaaccacacctacccagggctgccgcattcctgcactcagaagtctgcagcggtgcctcacaaacttgattgtgcataaaaatcactggggatcttgttaatacagattctaactcaatagatctgggagatcctgcatttctaacaagctcccaggtaaggcggaggctgctggtgtgaggaccatgctgtgagcagcagggcgagagtgcccagggctgatatatattggaaatatcacccctgaagccatcgctggcccccacctcctgtggactgatgccccagggattcccaccccacttctgcaaccccaggtatccttcattatccaccccatcccagactcccaccccagggattgcccgtgaagactttggcctagcaaattgtgttggttatgtgagtgttgttttaatcagagatgtacatgattgccaatctgcatttcttaccagtgtgaccacac 207 209101_atatcatcagatcgactcttatacgagtaatatgcctgctatttgaagtgtaattgagaaggaaaattttagcgtgctcactgacctgcctgtagccccagtgacagctaggatgtgcattctccagccatcaagagactgagtcaagttgttccttaagtcagaacagcagactcagctctgacattctgattcgaatgacactgttcaggaatcggaatcctgtcgattagactggacagcttgtggcaagtgaatttgcctgtaacaagccagattttttaaaatttatattgtaaatattgtgtgtgtgtgtgtgtgtgtatatatatatatatatgtacagttatctaagttaatttaaagttgtttgtgcctttttatttttgtttttaatgctttgatatttcaatgttagcctcaatttctgaacaccataggtagaatgtaaagcttgtctgatcgttcaaagcatgaaatggatacttatatggaaattctgctcagatagaatgacagtccgtcaaaacagattgtttgcaaaggggaggcatcagtgtcttg 208 209114_attacaccacaatggctgagcacttcctgacgttgctggtagtgcctgccatcaagaaagattatggttcccaggaagacttcactcaagtgtggaacaccaccatgaaagggctcaagtgctgtggcttcaccaactatacggattttgaggactcaccctacttcaaagagaacagtgcctttcccccattctgttgcaatgacaacgtcaccaacacagccaatgaaacctgcaccaagcaaaaggctcacgaccaaaaagtagagggttgcttcaatcagcttttgtatgacatccgaactaatgcagtcaccgtgggtggtgtggcagctggaattgggggcctcgagctggctgccatgattgtttccatgtatctgtactgcaatctacaataagtccacttctgcctctgccactactgctgccacatgggaaactgtgaagaggcaccctgggcaagcagcagtgattgggggaggggacaggatctaacaatgtcacttgggccagaatggacctggcctttctgctcccagacttgggggctag 209 209116_x_atgcagttatgggcaaccctaaggtgaaggctcatggcaagaaagtgctcggtgcctttagtgatggcctggctcacctggacaacctcaagggcacctttgccacactgagtgagctgcactgtgacaagctncangtggatcctgagaacttcaggctnctnggcaacgtgntngtctgngtgctggcccatcactttggcaaagaattcaccccaccag 210 209138_x_attctctgggctccaggctgaggacgaggctgattattactgctgctcatatgcaggtagttacactgtggttttcggcggagggaccaaactgaccgtcctaggtcagcccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagccaacaaggccacactggtgtgtctcataagtgacttctacccgggagccgtgacagtggcctggaaggcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaaagcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcccacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcccctacagaatgtt 211 209147_s_attttggtgcagctgctagtcagtccctgactgacattgccaagtattcaataggcagactgcggcctcacttcttggatgtttgtgatccagattggtcaaaaatcaactgcagcgatggttacattgaatactacatatgtcgagggaatgcagaaagagttaaggaaggcaggttgtccttctattcaggccactcttcgttttccatgtactgcatgctgtttgtggcactttatcttcaagccaggatgaagggagactgggcaagactcttacgccccacactgcaatttggtcttgttgccgtatccatttatgtgggcctttctcgagtttctgattataaacaccactggagcgatgtgttgactggactcattcagggagctctggttgcaatattagttgctgtatatgtatcggatttcttcaaagaaagaacttcttttaaagaaagaaaagaggaggactctcatacaactctgcatgaaacaccaacaactgggaatcactatccgagcaatcaccagc212 209156_s_atgcacgccatcaatgccatcgtgcgcagcccgcgtggcggggcccggaggcacgcagagctgtccttcgtgttcctcacggacggcgtcacgggcaacgacagtctgcacgagtcggcgcactccatgcgcaacgagaacgtggtacccaccgtcctggccttgggcagcgacgtggacatggacgtgctcaccacgctcagcctgggtgaccgcgccgccgtgttccacgagaaggactatgacagcctggcgcaacccggcttcttcgaccgcttcatccgctggatctgctagcgccgccgcccgggccccgcagtcgagggtcgtgagcccaccccgtccatggtgctaagcgggccc 213 209167_attgtttcctcatagctagttctcaagctgcatgtaagattttaacgggaagagaaaataggcctggacctgaaggtctcaaatatgttgagaagaaagtatgaactataaggaacttgagatgtagatttattttgcaggaaatacgaggaaaataggaaagaagtgtttgccgcatcaagtgtaaagaatgatactgaggatttttacattttatgaaatgaaataatggcatttacaaaatgaaaaatgtagtttcacaactaagttttgttaacagagactgcatgctttgcttatagttcttaattttggttttgacattcatttaattttttccatgttaaatatgtagtttaattatttactcaaaataaacattgttcatgcttttaggcctttgggggaattgatttttatccacaggtagaaaatggtctttgcacacactacacttatttcaaatatacaatgtgctcccgaactttcgcattagtctt 214 209170_s_atgaaatatcactgacactccagactaaagcagagtctaggtttctgcaattttgttacagtaatttgtaaatagctttagtaaactcaccttgcatggtagattaataagatgacttactgtacatgaattacacaataatgagatctggtggctatttccacattttgaaaaggattcagttatttactgacagtggtgagcatcctttttaaaataatgttctgatacttaaacattagagagcagtatctttaaatgaattattaacactttggaatacttacattttctgttatttttgattgcctgataaccagtttcaatgatgaaaatgaaaacaagtgctgaagatgaaatggaagagaaccgttttaatctggattttgttttgtcacacctggaaaatactttgcaaatatgttctaaattgaaaacaatttttttatgatcacatggttcactaccaaatgaccctcaaataagccagatg 215 209191_atgatagtcggaatagagccgccccaactcagatcctacaacacgcaagttccttcttgaaccctggtgcctcctaccctatggccctgaatggtgcactggtttaattgtgttggtgtcggcccctcacaaatgcagccaagtcatgtaattagtcatctggaacaaagactaaaaacagcagagaattgcgggttctacccagtcagaagatcacaccatggagactttctactagaggacttgaaagagaactgaggggccacaaaataaacttcaccttccattaagtgttcaagcatgtctgcaaattaggagggagttagaaacagtctttttcatcctttgtgatgaagcctgaaattgtgccgtgttgccttatatgaatatg216 209209_s_attgtctccccgctatctaaaaaagtataagaacaagcagataacagcgagaatcttggaggcccatcagaatgtagctcagatgagtctaattgaagccaagatgagatttattcaagcttggcagtcactacctgaatttggcatcactcacttcattgcaaggttccaagggggcaaaaaagaagaacttattggaattgcatacaacagactgattcggatggatgccagcactggagatgcaattaaaacatggcgtttcagcaacatgaaacagtggaatgtcaactgggaaatcaaaatggtcaccgtagagtttgcagatgaagtacgattgtccttcatttgtactgaagtagattgcaaagtggttcatgaattcattggtggctacatatttctctcaacacgtgcaaaagaccaaaacgagagtttagatgaagagatgttctacaaacttaccagtggttgggtgtgaatagaaatactgtttaatgaaactccacggccataa217 209210_s_ataaaatgctattagtccgtcgtgcttnatttgtttttgtccttgaataagcatgttatgtatatngtctcgtgtttttatttttacaccatattgtattacacttttagtattcaccagcataancactgtctgcctaaaatatgcaactctttgcattacaatatgaagtaaagttctatgaagtatgcattttgtgtaactaatgtaaaaacacaaattttataaaattgtacagttttttaaaaactactcacaactagcagatggcttaaatgtagcaatctctgcgttaattaaatgcctttaagagatataattaacgtgcagttttaatatctactaaattaagaatgacttcattatgatcatgatttgccacaatgtccttaactctaatgcctggactggccatgttctagtctgttgcgctgttacaatctgtattggtgctagtcagaaaattcctagctcacatagcccaaaagggtgcgagggagaggtggattaccagtattgttcaataatccatggttca218 209283_atgaccagttcttcggagagcacctgttggagtctgatcttttcccgacgtctacttccctgagtcccttctaccttcggccaccctccttcctgcgggcacccagctggtttgacactggactctcagagatgcgcctggagaaggacaggttctctgtcaacctggatgtgaagcacttctccccagaggaactcaaagttaaggtgttgggagatgtgattgaggtgcatggaaaacatgaagagcgccaggatgaacatggtttcatctccagggagttccacaggaaataccggatcccagctgatgtagaccctctcaccattacttcatccctgtcatctgatggggtcctcactgtgaatggaccaaggaaacaggtctctggccctgagcgcaccattcccatcacccgtgaaaagaagcctgctgtcaccgcagcccccaagaaaaagatgccctttcttgaattgcattttttaaaacaagaaagtttccccaccagtgaatgaa219 209301_attgaatcttcgggtgtttccctttagctaagcacagatctaccttggtgatttggaccctggttgctttgtgtctagttttctagacccttcatctcttacttgatagacttactaataaaatgtgaagactagaccaattgtcatgcttgacacaactgctgtggctggttggtgctttgtttatggtagtagtttttctgtaacacagaatataggataagaaataagaataaagtaccttgactttgttcacagcatgtagggtgatgagcactcacaattgttgactaaa 220209312_x_atctgtgtatccttcaaagacccagcccctgcagcaccataacctcctggtctgttctgtgagtggtttctatccaggcagcattgaagtcaggtggttccggaatggccaggaagagaagactggggtggtgtccacaggcctgatccacaatggagactggaccttccagaccctggtgatgctggaaacagttcctcggagtggagaggtttacacctgccaagtggagcacccaagcgtgacaagccctctcacagtggaatggagagcacggtctgaatctgcacagagcaagatgctgagtggagtcgggggctttgtgctgggcctgctcttccttggggccgggctgttcatctacttcaggaatcagaaaggacactctggacttcagcca221 209335_atagtcaaatgccaaacactagctctgtattaatccccatcattactggtaaagcctcatttgaatgtgtgaattcaatacaggctatgtaaaatttttactaatgtcattattttgaaaaaataaatttaaaaatacattcaaaattannannnnanacaagcttaattgttaatattccctaaacacaattttatgaagggagaagacattggtttgttgacaataacagtacatcttttcaagttctcagctatttcttctacctctccctatcttacatttgagtatggtaacttatgtcatctatgttgaatgtaagcttataaagcacaaagcatacatttcctgactggtctagagaactgatgtttcaatttacccctctgctaaataaa 222209357_atggcaaactgcttaatcttgtggattttgtagatggtttcaaatgactgaactgcattcagatttacgagtgaaaggaaaaattgcattagttggttgcatgaactttgaagggcagatattactgcacaaactgccatctcgcttcatttttttaactatgcatttgagtacagactaatttttaaaatatgctaaactggaagattaaacagatgtggcccaaactgttctggatcaggaaagtcatactgttcactttcaagttggctgtcccccccgccgcccccccccacccccatatgtacagatgataatagggtgtggaatgtcgtcagtggcaaacatttcacagattattttgtttctgtcttcaacatttttgacactgtgctaat 223209373_atctcctccatgagtctgacatctcggaaactgagcagctgccggacgcctgggtcaggaatccaagaccccacctcttaaggactggttcctcagaaagcaccctcagggaaaaaggtgaaaacattacatccgtggattctcctgccacaaccgcattggaagaaaaggctgccgcaacatctcagcgaggagtgaaggacccatgtcccaggaaccgcgctgcgccacctgcactcacccccctcacattctcttaagcacccggtggccctccgaggcctggcggaatggtggtgcccacggggttgggcaagggctcaccaggacctcaacgggcaaagttgtgcacactaaaatatcaaatcaaggtgcttggttttaaagtaaatgtttttctaaagaaagctgtgttcttctgttgacccagacgaatagggcacagccctgtaactgcacgtgccttctgtcattgggaatg 224209374_s_atcaccatcacgtgcctggtgacgggcttctctcccgcggacgtcttcgtgcagtggatgcagagggggcagcccttgtccccggagaagtatgtgaccagcgccccaatgcctgagccccaggccccaggccggtacttcgcccacagcatcctgaccgtgtccgaagaggaatggaacacgggggagacctacacctgcgtggtggcccatgaggccctgcccaacagggtcaccgagaggaccgtggacaagtccacc 225 209436_atttcttttttatattgtcctccacctccatcattttcaataaaagatagggcttttgctcccttgttcttggagggaccattattacatctctgaactacctttgtatccaacatgttttaaatccttaaatgaattgctttctcccaaaaaaagcacaatataaagaaacacaagatttaattatttttctacttggggggaaaaaangtcctcatgtagaagcacccacttttgcaatgttgttaagctatctatctanctctcagcccatgataaagttccttaagctggtgattcctaatcaaggacaagccacccaccctagtgtctcatgtttgtat 226 209457_atggaagcacaatttccaccttattttttgaactttggcagtttcaatgtctgtctctgttgcttcggggcataagctgatcaccgtctagttgggaaagtaaccctacagggtttgtagggacatgatcagcatcctgatttgaaccctgaaatgttgtgtagacaccctcttgggtccaatgaggtagttggttgaagtagcaagatgttggcttttctggattttttttgccatgggttcttcactgaccttggactttggcatgattcttagtcatacttgaacttgtctcattccacctcttctcagagcaactcttcctttgggaaaagagttcttcagatcatagaccaaaaaagtcataccttcgaggtggtagcagtagattccaggaggagaagggtacttgctaggtatcctgggtcagtggcggtgcaaactggtttcctcagctgcctgtccttctgtgtgcttatgtctcttgtgacaattgttttcctccct 227209458_x_atagagaacccaccatggtgctgtctcctgccgacaagaccaacgtcaaggccgcctggggtaaggtcggcgcgcacgctggcgagtatggtgcggaggccctggagaggatgttcctgtccttccccaccaccaagacctacttcccgcacttcgacctgagccacggctctgcccaggttaagggccacggcaagaaggtggccgacgcgctgaccaacgccgtggcgcacgtggacgacatgcccaacgcgctgtccgccctgagcgacctgcacgcgcacaagcttcgggtggacccggtcaacttcaagctcctaagccactgcctgctggtgaccctggccgcccacctccccgccgagttcacccctgcggtgcacgcctccctggacaagttcctggcttctgtgagcaccgtgctgacctccaaataccgttaagctg 228 209496_attggaggaatttcacaagcacccgcccgtgcagtgggccttccaggagaccagtgtggagagcgccgtggacacgcccttcccagctggaatatttgtgaggctggaatttaagctgcagcagacaagctgccggaagagggactggaagaaacccgagtgcaaagtcaggcccaatgggaggaaacggaaatgcctggcctgcatcaaactgggctctgaggacaaagttctgggccggttggtccactgccccatagagacccaagttctgcgggaggctgaggagcaccaggagacccagtgcctcagggtgcagcgggctggtgaggacccccacagcttctacttccctggacagttcgccttctccaaggccctgccccgcagctaagccagcactgagctgcgtggtgcctccaggaccgctgccggtggtaaccagtggaagaccccagcccccagggagaggaccccgttctatccccagccatgataata229 209498_attttgtcaggaaaccttggcctctgctaaggtgtatttggtccttgagaagtgggagcaccctacagggacactatcactcatgctggtggcattgtttacagctagaaagctgcactggtgctaatgccccttggggaaatggggctgtgaggaggaggattataacttaggcctagcctcttttaacagcctctgaaatttatcttttcttctatggggtctataaatgtatcttataataaaaaggaaggacaggaggaagacaggcaaatgtacttctcacccagtcttctacacagatggaatctctttggggctaagagaaaggttttattctatattgcttacctgatctcatgttaggcctaagaggctttctccaggaggattagcttggagttctctatactcaggtacctctttcagggttttctaaccctgacacggactgtgcatactttccc 230 209612_s_atactggatgcgttaataacccatgttttaccttttgaaaaaataaatgaaggatttgacctgcttcactctgggaaaagtatccgtaccgtcctgacgttttgaggcaatagagatgccttcccctgtagcagtcttcagcctcctctaccctacaagatctggagcaacagctaggaaatatcattaattcagctcttcagagatgttatcaataaattacacatgggggctttccaaagaaatggaaattgatgggaaattatttttcaggaaaatttaaaattcaagtgagaagtaaataaagtgttgaacatcagctggggaattgaagccaacaaaccttccttcttaaccattctactgtgtcacctttgccattgaggaaaaatattcctgtgacttcttgcatttttggtatcttcataatctttagtcatcgaatcccagtggaggggacccttttacttgccctgaacatacacatgctgggccattgtgattgaagtcttctaactctgtctcagt231 209613_s_atgcagatttcttgcttcatatgacaaagcctcaattactaattgtaaaaactgaactattcccagaatcatgttcaaaaaatctgtaatttttgctgatcgaaagtgcttcattgactaaacagtattagtttgtggctataaatgattatttagatgatgactgaaaatgtgtataaagtaattaaaagtaatatggtggctttaagtgtagagatgggatggcaaatgctgtgaatgcagaatgtaaaattggtaactaagaaatggcacaaacaccttaagcaatatattttcctagtagatatatatatacacatacatatatacacatatacaaatgtatatttttgcaaaattgttttcaatctagaacttttctattaactaccatgtcttaaaatcaagtctataatcctagcattagtttaatattttgaatatgtaaacacctgtgttaatgctttgttaatgcttttcccactctcatttgttaatgctttcccactctcgggaaggatttgcattttgagctttatctctaaatgtgacatgca232 209621_s_atggatgccgctctgtgacaaatgtggcagtggcatagtcggtgctgtggtgaaggcgcgggataagtaccggcaccctgagtgcttcgtgtgtgccgactgcaacctcaacctcaagcaaaagggctacttcttcatagaaggggagctgtactgcgaaacccacgcaagagcccgcacaaaacccccaagaggctatgacacggtcactctgtatcccaaagcttaagtctctgcaggcgtggcacacgcacgcacccacccacgcgcacttacacgagaagacattcatggctttgggcagaaggattgtgcagattgtcaactccaaatctaaagtcaaggctttagacctttatcctattgtttattgaggaaaaggaatgggaggcaaatgcctgctatgtgaaaaaaacatacacttagctatgttttgcaactctttttggggctag 233 209651_atttcctgaagctcttcggctgacagcccgctcggctcgccctctcccccggaggccgcgccctcccggaaaagccgggtcctccagaccccgaggccttgctctcagagcgggaggccccacccactggagagccccgcccctaaggtactatgagttctcaggggtcaagttcagaaacggcccagccagacctaaacccacacgcccacaaagtggattgcacacagacaagaactcccgtgcgggcctccactctattcccacccttgagggagcccccttactgggggagggtccttgcaattccagcgaatcggaggccaggccaggacgtccttgctccctgcaccctcactgttctgtgcactttttctacctacataaacacacgcatt234 209656_s_atgcagggctagttattccgatttcttgcacaattatttagctttttgtaagttcaacatgtaaattttaaagacataaatatagagagacttatgtgtttgaatataaatgatatatatggattagcatgtacctgtatattattaaacatgcaatgaactgactggtaagtgacgtctaattgtatggctagcaatgtaatttattcagactgtatttttgtacagagcagtgcactctaacctatgcctctgtgtcctctttaatgcctaaagctgtgcctagaaatttcatctgtcttaaaagtaaaatatacttcatgctgtttatgctattagtttctgtactgctattctatatttattatttttaaatatatgacatgtttactacttaaacatgaattcatggtatcctggttattttttttaagtcatctgggggaaaacctgtttatcactccagtgattttgagtttgcagtttcacaatcagttcttcat 235 209667_atcaggccttttccactttgagggaggtgcttcgaagaatgttgcccacacctaagtgttagaagcctatgtccgttcatccctgagaggtctgaa236 209668_x_attggcggactccatgtttgtgatccctgcactccaagtagcacattttcagtgttcccgggcccctgtgtacttctacgagttccagcatcagcccagctggctcaagaacatcaggccaccgcacatgaaggcagaccatggtgatgagcttccttttgttttcagaagtttctttgggggcaactacattaaattcactgaggaagaggagcagctaagcaggaagatgatgaagtactgggccaactttgcgagaaatgggaacccgaatggcgagggtctgccacactggccgctgttcgaccaggaggagcaatacctgcagctgaacctacagcctgcggtgggccgggctctgaaggcccacaggctccagttctggaagaaggcgctgccccaaaagatccaggagctcgaggagcctgaagagagacacacagagctgtagctccctgtgccggggaggagggggtgggttcgctgacaggcgagggtcagcctgctgtg237 209687_atgagagctcgctttgagtgactgggttttgtgattgcctctgaagcctatgtatgccatggaggcactaacaaactctgaggtttccgaaatcagaagcgaaaaaatcagtgaataaaccatcatcttgccactaccccctcctgaagccacagcagggtttcaggttccaatcagaactgttggcaaggtgacatttccatgcataaatgcgatccacagaaggtcctggtggtatttgtaactttttgcaaggcatttttttatatatatttttgtgcacatttttttttacgtttctttagaaaacaaatgtatttcaaaatatatttatagtcgaacaattcatatatttgaagtggagccatatgaatgtcagtagtttatacttctctattatctcaaactactggcaatttgtaaagaaatatatatgatatataaatgtgattgcagcttttcaatgttagccacagt 238 209735_attgtggtttctgtagcaacacttctcatgaccatctgttttgtgtttatgatgattttttcaggtctgttggtcaatctcacaaccattgcatcttggctgtcatggcttcagtacttcagcattccacgatatggatttacggctttgcagcataatgaatttttgggacaaaacttctgcccaggactcaatgcaacaggaaacaatccttgtaactatgcaacatgtactggcgaagaatatttggtaaagcagggcatcgatctctcaccctggggcttgtggaagaatcacgtggccttggcttgtatgattgttattttcctcacaattgcctacctgaaattgttatttcttaaaaaatattcttaaatttccccttaattcagtatgatttatcctcacataaaaaagaagcactttgattgaagtattcaatcaagttttttgttgttttctgttcccttgccatcacactgttgcacagca 239 209763_atgaacacgcagagagtttccctagatatactcctgcctccaggtgctgggacacacctttgcaaaatgctgtgggaagcaggagctggggagctgtgttaagtcaaagtagaaaccctccagtgtttggtgttgtgtagagaataggacatagggtaaagaggccaagctgcctgtagttagtagagaagaatggatgtggttcttcttgtgtatttatttgtatcataaacacttggaacaacaaagaccataagcatcatttagcagttgtagccattttctagttaactcatgtaaacaagtaagagtaacataacagtattaccctttcactgttctcacaggacatgtacctaattatggtacttatttatgtagtcactgtatttctggattttt240 209791_atctccagccccagagctgaaaacaccaagtgcctatttgagggtgtctgtctggagacttagagtttgtcatgtgtgtgtgtgtnnttggttaatgtgggtttatgggttttctttctttttttttttttttttttnnagtctacattagggggaagtgagcgcctcccatgtgcagacagtgtgtctttatagatttttctaaggctttccccaatgatgtcggtaatttctgatgtttctgaagttcccaggactcacacacccgttcccatctcacttgcccacccagtgtgacaaccctcggtgtggatatacccccgtggactcatggctcttccccacccccactttctataaatgtaggcctagaatacgcttctctgttgcaaaactcagctaagttcctgcttccaccttgatgttgaaatatcttatgtaagagggcaggggatgtcgtgaagatggc 241 209868_s_atggaatgacacttacttacgacccaactacagctgctatacagaacggattttatccttcaccatacagtattgctacaaaccgaatgatcactcaaacttctattacaccctatattgcatctcctgtatctgcctaccaggtgcaaagtccttcgtggatgcaacctcaaccatatattctacagcaccctggtgccgtgttaactccctcaatggagcacaccatgtcactacagcccgcatcaatgatcagccctctggcccagcagatgagtcatctgtcactaggcagcaccggaacatacatgcctgcaacgtcagctatgcaaggagcctacttgccacagtatg 242 209948_atggaacgaaaccagcgtcctattccagcgcctctacgggccccaggccctcctcttctccctcttctggcccaccttcctgctgaccggtggcctcctcattatcgccatggtgaagagcaaccagtacctgtccatcctggcggcccagaagtagagccatccatccatgccataccacttgtcagggcacaggggactggctgggcccccagggctgctccccacttgcagcacaatgccttctccacctgccctcccactcttccagtccaatccacgctgtcttctgttgcaggactaacctttgagaaatccttttgtgaagtcattgcctgctcaagaatgtacagtggctccccaatgccttggagccataaggccagccagttctagctctctattacctgtccccactcaactgactcatacctgtttccggctgcatcactatgtgccccacagagaacgatgatcgtcacctctgtgcctgagttctccctgttgtctcaaagcggtacc243 210084_x_atccggtcagcaggatcatcgtgcacccacagttctacatcatccagactggagcggatatcgccctgctggagctggaggagcccgtgaacatctccagccgcgtccacacggtcatgctgccccctgcctcggagaccttccccccggggatgccgtgctgggtcactggctggggcgatgtggacaatgatgagcccctcccaccgccatttcccctgaagcaggtgaaggtccccataatggaaaaccacatttgtgacgcaaaataccaccttggcgcctacacgggagacgacgtccgcatcatccgtgacgacatgctgtgtgccgggaacacccggagggactcatgccagggcgactctggagggcccctggtgtgcaaggtgaatggcacctggctacaggcgggcgtggtcagctgggacgagggctgtgcccagcccaaccggcctggcatctacacccgtgtcacctactacttggactggatccaccactatgtccccaaaaagccgtgagtcaggcctggggtgt 244 210107_atggccaaatcaccgacctgaaggcggaaattcacgggggcagtctcattaatctgacttggacagctcctggggatgattatgaccatggaacagctcacaagtatatcattcgaataagtacaagtattcttgatctcagagacaagttcaatgaatctcttcaagtgaatactactgctctcatcccaaaggaagccaactctgaggaagtctttttgtttaaaccagaaaacattacttttgaaaatggcacagatcttttcattgctattcaggctgttgataaggtcgatctgaaatcagaaatatccaacattgcacgagtatctttgtttattcctccacagactccgccagagacacctagtcctgatgaaacgtctgctccttgtcctaatattcatatcaacagcaccattcctggcattcacattttaaaaattatgtggaagtggataggagaactgcagctgtcaatagcctagggc 245 210133_ataccccttcagcgactagagagctacaggagaatcaccagtggcaaatgtccccagaaagctgtgatcttcaagaccaaactggccaaggatatctgtgccgaccccaagaagaagtgggtgcaggattccatgaagtatctggaccaaaaatctccaactccaaagccataaataatcaccatttttgaaaccaaaccagagcctgagtgttgcctaatttgttttcccttcttacaatgcattctgaggtaacctcattatcagtccaaagggcatgggttttattatatatatatatattttttttttaaaaaaaaacgtattgcatttaatttattgaggctttaaaacttatcctccatgaatatcagttatttttaaactgtaaagctttgtgcagattctttaccccctgggagccccaattcgatcccctgtcacgtgtgggcaatgttccccc 246 210139_s_attgtgaagctttacgcgcacacggacaaaatgcccaaactggagcccttgcaaaaacacggcttgtggcattggcatacttgcccttacaggtggagtatcttcgtcacacatctaaatgagaaatcagtgacaacaagtctttgaaatggtgctatggatttaccattccttattatcactaatcatctaaacaactcactggaaatccaattaacaattttacaacataagatagaatggagacctgaataattctgtgtaatataaatggtttataactgcttttgtacctagctaggctgctattattactataatgagtaaatcataaagccttcatcactcccacatttttcttacggtcggagcatcagaacaagcgtctagactccttgggaccgtgagttcctagagcttggctgggtctaggctgttctgtgcctccaaggactgtctggcaatgacttgtattggccaccaactgtagatgtatatatggtgcccttctgatgctaagactccagaccttttgt247 210298_x_attctactgcgtgacttgccatgagaccaagtttgccaagcattgcgtgaagtgcaacaaggccatcacatctggaggaatcacttaccaggatcagccctggcatgccgattgctttgtgtgtgttacctgctctaagaagctggctgggcagcgtttcaccgctgtggaggaccagtattactgcgtggattgctacaagaactttgtggccaagaagtgtgctggatgcaagaaccccatcactgggaaaaggactgtgtcaagagtgagccgcccagtctctaaagctaggaagcccccagtgtgccacgggaaacgcttgcctctcaccctgtttcccagcgccaacctccggggcaggcatccgggtggagagaggacttgtccctcgtgggtggtggttctttatagaaaaaatcgaagcttagcagctcctcgtggcccgggtttggtaaaggctccagtgtggtggcctatgaaggacaatcctggcacgactactgcttccactgcaaaaaatgctccgtgaatctggccaacaagcgctttgttttccacc 248 210299_s_atgcataggagataaaacccccactgagatgctctcatgcctcagctggacccaccgtgtagacacacgacatgcaagagttgcagcggctgctccaactcactgctcaccctctctgtgagcagaaagaaccctactgacatgcatggttaacttcctcatcagaactctgcccttcccttctgttcttttgtgctttcaaataactaacacgaacttccagaaaattaacatttgaacttagctgtaattctaaactgacctttccccgtactaacgtttggtttccccgtgtggcatgcttttctgagccttcctactttaaagcatggaacatgcaggtgatttgggaagtgtagaaagacctgagaaaacgagcctgtttcagaggaacatcgtcacaacgaatacttctggaagcttaacaaaactaaccctgctgtcctt 249 210302_s_atatttcgttttgcttttggttgcctgaatgttgtcaccaagtgaaaaaattatttaactatatgtaaaatttctcttttaaaaaaaagttttactgatgttaaacgttctcagtgccaatgtcagactgtgctcctccctctcctgaacctctaccctcaccctgagctgtcttgttgaaaacagt250 210495_x_atagccctttgctctggaggaagttctccagcttcagctcaactcacagcttctccaagcatcaccctgggagtttcctgagggttttctcataaatgagggctgcacattgcctgttctgcttcgaagtattcaataccgctcagtattttaaatgaagtgattctaagatttggtttgggatcaataggaaagcatatgcagccaaccaagatgcaaatgttttgaaatgatatgaccaaaattttaagtaggaaagtcacccaaacacttctgctttcacttaagtgtctggcccgcaatactgtaggaacaagcatgatcttgttactgtgatattttaaatatccacagtactcactttttccaaatgatcctagtaattgcctagaaatatctttctcttacctgttatttatcaatttttcccagtatttttatacggaaaaaattgtattgaaaacacttagtatgcagttgataagaggaatttggtataattatggtgggtgattattttttatactgtatgtgccaaagctttactactgtg251 210517_s_atgtgccatagtgcaggcttggggagctttaagcctcagttatataacccacgaaaaacagagcctcctagatgtaacattcctgatcaaggtacaattctttaaaattcactaatgattgaggtccatatttagtggtactctgaaattggtcactttcctattacacggagtgtgctaaaactaaaaagcattttgaaacatacagaatgttctattgtcattgggaaatttttctttctaacccagtggaggttagaaagaagttatattctggtagcaaattaactttacatcctttttcctacttgttatggttgtttggaccgataagtgtgcttaatcctgaggcaaagtagtgaatatgttttatatgttatgaagaaaagaattgttgtaagtttttgattctactcttatatgctggactgcattcacacatggcatgaaataagtcaggttctttacaaatggtattttgatagatactggattgtgtttgtgccatatttgtgccatt252 210524_x_atgtcaggactgttatggccctgttgtgctgagttagttggaacagaattcaagctccctgcactagtccacctgccccactgcttcttcgcttctctcttggaaagtccagtctctcctcggcttgcaatggaccccaactgctcctgcgccgctggtgtctcctgcacctgcgctggttcctgcaagtgcaaagagtgcaaatgcacctcctgcaagaagagctgctgctcctgctgccccgtgggctgtagcaagtgtgcccagggctgtgtttgcaaaggggcgtcagagaagtgcagctgctgcgactgatgccaggacaacctttctcccagatgtaaacagagagacatgtacaaacctggattttttttttataccaccttgacccatttgctacattccttttcctgtgaaa253 210735_s_atcaggaaggaccttgctttggaccctacacacttcggctctctggacacttgcgacacctcaaggtgttctctgtagctcaatctgcaaacatgccaggcctcagggatcctctgctgggtgcctccttgccttgggaccatggccaccccagagccatccgatcgatggatgggatgcactctcagaccaagcagcaggaattcaaagctgcttgctgtaactgtgtgagattgtgaagtggtctgaattctggaatcacaaaccaagccatgctggtgggccattaatggttggaaaacactttcatccggggctttgccagagcgtgctttcaagtgtcctggaaagtctgctgcttctccaagctttcagacaagaatgtgcactctctgcttaggttttgcttgggaaactcaacttctttcctctggagacggggcatctccctctgatttccttctgctatgacaaaacctttaatctgcaccttacaactcggggacaa254 210764_s_atttaccaatgacaaccctgagtgccgccttgtgaaagaaacccggatttgtgaggtgcggccttgtggacagccagtgtacagcagcctgaaaaagggcaagaaatgcagcaagaccaagaaatcccccgaaccagtcaggtttacttacgctggatgtttgagtgtgaagaaataccggcccaagtactgcggttcctgcgtggacggccgatgctgcacgccccagctgaccaggacatgtgaagatgcggttccgctgcgaagatggggagacattttccaagaacgtcatgatgatccagtcctcaaatgcaactacaactgcccgcatgccaatgaagcagcgtttcccttctacaggctgttcaatgacattcacaaatttagggactaaatgctacctgggtttccagggcacacctagacaaacaagggagaagagtgtcagaatcagaatcatggagaaaatgggcgggggtggtgtgggtgatgggactcattgtagaaaggaagccttgctcattcttgaggagcattaaggtatttcgaaactgccaagggtgc 255 210809_s_ataaattgtggagttagcctcctgtggagttagcctcctgtggtaaaggaattgaagaaaatataacaccttacaccctttttcatcttgacattaaaagttctggctaactttggaatccattagagaaaaatccttgtcaccagattcattacaattcaaatcgaagagttgtgaactgttatcccattgaaaagaccgagccttgtatgtatgttatggatacataaaatgcacgcaagccattatctctccatgggaagctaagttataaaaataggtgcttggtgtacaaaactttttatatcaaaaggctttgcacatttctatatgagtgggtttactggtaaattatgttattttttacaactaattttgtactctcagaatgtttgtcatatgcttcttgcaatgc256 210946_ataaggcaagaggatgcatctttcttcctggtgtacaagcctttaaagacttctgctgctgatatgcctcttggatgcacactttgtgtgtacatagttacctttaactcagtggttatctaatagctctaaactcattaaaaaaactccaagccttccaccaaaacagtgccccacctgtatacatttttattaaaaaaatgtaatgcttatgtataaacatgtatgtaatatgctttctatgaatgatgtttg 257 210982_s_atgaaggagacggtctggcggcttgaagaatttggacgatttgccagctttgaggctcaaggtgcattggccaacatagctgtggacaaagccaacttggaaatcatgacaaagcgctccaactatactccgatcaccaatgacaagttcaccccaccagtggtcaatgtcacgtggcttcgaaatggaaaacctgtcaccacaggagtgtcagagacagtcttcctgcccagggaagaccaccttttccgcaagttccactatctccccttcctgccctcaactgaggacgtttacgactgcagggtggagcactggggcttggatgagcctcttctcaagcactgggagtttgatgctccaagccctctcccagagactacagagaacgtggtgtgtgccctgggcctgactgtgggtctggtgggcatcattattgggaccatc 258 211161_s_ataatattggatatcaactgcttgtaaaggtgctcctcctttttcttgtcattgctggtcaagattactaatatttgggaaggctttaaagacgcatgttatggtgctaatgtactttcacttttaaactctagatcagaattgttgacttgcattcagaacataaatgcacaaaatctgtacatgtctcccatcagaaagattcattggcatgccacaggggattctcctccttcatcctgtaaaggtcaacaataaaaaccaaattatggggctgcttttgtcacactagcatagagaatgtgttgaaatttaactttgtaagcttgtatgtggttgttgatcttttttttccttacagacacccataat 259 211372_s_atatctcatacccgcaaattttaaccttgtcaacctctggggtattagtatgccctgacctgagtgaattcacccgtgacaaaactgacgtgaagattcaatggtacaaggattctcttcttttggataaagacaatgagaaatttctaagtgtgagggggaccactcacttactcgtacacgatgtggccctggaagatgctggctattaccgctgtgtcctgacatttgcccatgaaggccagcaatacaacatcactaggagtattgagctacgcatcaagaaaaaaaaagaagagaccattcctgtgatcatttcccccctcaagaccatatcagcttctctggggtcaagactgacaatcccgtgtaaggtgtttctgggaaccggcacacccttaaccaccatgctgtggtggacggccaatgacacccacatagagagcgccta 260 211538_s_atagctcgaaagagtttgcaaccccatcatcagcaaactttaccaaggtggtcctggcggcggcagcggcggcggcggttcaggagcctccgggggacccaccatcgaagaagtggactaagcttgcactcaagtcagcgtaaacctctttgcctttctctctctctctttttttttgtttgtttctttgaaatgtccttgtgccaagtacgagatctattgttggaagtctttggtatatgcaaatgaaaggagaggtgcaacaacttagtttaattataaaagttccaaagtttgttttttaaaaacattattcgaggtttctctttaatgcattttgcgtgtttgctgacttgagcatttttgattagttcgtgcatggagatttgtttgagatgagaaaccttaagtttgcacacctgttctgtagaagcttg261 211548_s_atgctttttttgttgtcagctatcttaagaatcattaaatacacctgctttgggtaaaactctttgcaagcagtaattaacactagtaacagtgaaagcacaagatttccaaatcagtcgttttctcaaaaaaatatcgtataagtgactcatcctgtctgctaactccagacctcccagcttgaagccaaatctttccatgtgagattgatatggatttcctagaagtactggaatgttgtcatatcttgccctattttaattctgctatagaaaacaattgccttcacttttaaggagtaatttgaatattaataactctggtctagattttcatataatgtattaaagacaaagtagtgaacatcaatgaacatctgatagagataaactgtaatcaggcataagcttgtttgtatgttctggcagtgactaatcagtaaatgatgtcggtttgcccagtatcacttatcttctg 262 211549_s_atcgtgaacggcaaagtggcgctggtgaccggcgcggctcagggcataggcagagcctttgcagaggcgctgctgcttaagggcgccaaggtagcgctggtggattggaatcttgaagcaggtgtacagtgtaaagctgccctggatgagcaatttgaacctcagaagactctgttcatccagtgcgatgtggctgaccagcaacaactgagagacacttttagaaaagttgtagaccactttggaagactggacattttggtcaataatgctggagtgaataatgagaaaaactgggaaaaaactctgcaaattaatttggtttctgttatcagtggaacctatcttggtttggattacatgagtaagcaaaatggaggtgaaggcggcatcattatcaatatgtcatctttagcagcccaccattgattgccaatggattgataacactcattgaagatgatgctttaaatggtgctattatgaagatcacaacttctaagggaattcattttcaagactatgatacaactccatttcaag 263 211596_s_atgagtattacattggccttgggggacagaaaggaggaagttctgacttttcagggctaccttatttctactaaggacccagagcaggcctgtccatgccattccttcgcacagatgaaactgagctgggactggaaaggacagcccttgacctgggttctgggtataatttgcacttttgagactggtagctaaccatcttatgagtgccaatgtgtcatttagtaaaacttaaatagaaacaaggtccttcaaatgttcctttggccaaaagctgaagggagttactgagaaaatagttaacaattactgtcaggtgtcatcactgttcaaaaggtaagcacatttagaattttgttcttgacagttaactgactaatcttacttccacaaaatatgtgaatttgctgcttctgagaggca264 211637_x_atggactggtgaagccttcggagaccctgtccctcacctgcagtgtctctggtggctccatcagtagttactactggagctggatccggcagcccccagggaagggactggagtggattgggtatatcaattacagtgggagcaccaactataacccctccctcaagagtcgagtcaccatatcagtagacacgtccaagaaccagttctccctgaagctgagctctgtgaccgctgcggacacggccgtgtattactgtgcgagaacgatttcggggggtcg265 211643_x_ataatagtgatgacgcagcttccagccaccctgtctgtgtctccaggggaaagagccaccctctcctgcagggccagtcagagtgttcgcagcaacttagcctggtaccagcaaaaacctggccaggctcccaggctcctcatctacggtgcatccaccagggccaatggtatcccagccaggttcagtggcagtgggtctgggacagagttcactctcaccatcagcggcctgcagtctgacgattttgcagtttattactgtcaacactataataactggcctccgtggacgt266 211644_x_ataattgtgttgacgcagtctccaggcaccctgtctttgtctccaggggaaagagccaccctctcctgcagggccagtcagagtattagcagcagtttcttagcctggtaccagcagaaagttggccaggctcccaggctcctcatctatggtgcatccagcagggccactggcatcccagacaggttcagtggcagtgggtctgggacagacttcactctcaccatcagcagactggagcctgaagattttgcagtgtattactgtcagcaatatggtagctcgc267 211645_x_attcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggcaagtcagggcattagaaatgatttagcctggtatcagcagaaaccagggaaagcccctaagcgcctgatctatgctgcatccagtttgcaaagtggggtcccatcaaggttcagcggcagtggatctgggacagaattcactctcacaatcagcagcctgcagcctgaagattttgcaacttattactgtctacagcataatagttacccttg 268 211671_s_atgcagttgagtcgtcatcacttttcagtgatgggagagtagatggtgaaatttattagttaatatatcccagaaattagaaaccttaatatgtggacgtaatctccacagtcaaagaaggatggcacctaaaccaccagtgcccaaagtctgtgtgatgaactttctcttcatactttttttcacagttggctggatgaaattttctagactttctgttggtgtatcccccccctgtatagttaggatagcatttttgatttatgcatggaaacctgaaaaaaagtttacaagtgtatatcagaaaagggaagttgtgccttttatagctattactgtctggttttaacaatttcctttatatttagtgaactacgcttgctcattttttcttacataattttttattcaagttattgtacagctgtttaagatgggcagctagttcgtagctttccca 269 211696_x_attgaggagaagtctgccgttactgccctgtggggcaaggtgaacgtggatgaagttggtggtgaggccctgggcaggctgctggtggtctacccttggacccagaggttctttgagtcctttggggatctgtccactcctgatgctgttatgggcaaccctaaggtgaaggctcatggcaagaaagtgctcggtgcctttagtgatggcctggctcacctggacaacctcaagggcacctttgccacactgagtgagctgcactgtgacaagctgcacgtggatcctgagaacttcaggctcctgggcaacgtgctggtctgtgtgccggcccatcactttggcaaagaattcacccaaccagtgcaggctgcctatcagaaagtggtggctggtgtggctaatgccctggcccacaagtatcactaagctcgctttcttgctgtccaatttctattaaaggttcctttgttccctaagtccaactactaaactg270 211699_x_atagagaacccaccatggtgctgtctcctgacgacaagaccaacgtcaaggccgcctggggtaaggtcggcgcgcacgctggcgagtatggtgcggaggccctggagaggatgttcctgtccttccccaccaccaagacctacttcccgcacttcgacctgagccacggctctgcccaggttaagggccacggcaagaaggtggccgacgcgctgaccaacgccgtggcgcacgtggacgacatgcccaacgcgctgtccgccctgagcgacctgcacgcgcacaagcttcgggtggacccggtcaacttcaagctcctaagccactgcctgctggtgaccctggccgcccacctccccgccgagttcacccctgcggtgcacgcctccctggacaagttcctggcttctgtgagcaccgtgctgacctccaaataccgttaagctg 271 211719_x_atgggagtttcctgagggttttctcataaatgagggctgcacattgcctgttctgcttcgaagtattcaataccgctcagtattttaaatgaagtgattctaagatttggtttgggatcaataggaaagcatatgcagccaaccaagatgcaaatgttttgaaatgatatgaccaaaattttaagtaggaaagtcacccaaacacttctgctttcacttaagtgtctggcccgcaatactgtaggaacaagcatgatcttgttactgtgatattttaaatatccacagtactcactttttccaaatgatcctagtaattgcctagaaatatctttctcttacctgttatttatcaatttttcccagtatttttatacggaaaaaattgtattgaaaacacttagtatgcagttgataagaggaatttggtataattatggtgggtgattattttttatactgtatgtgccaaagctttactactgtg 272 211745_x_attcctgccgacaagaccaacgtcaaggccgcctggggtaaggtcggcgcgcacgctggcgagtatggtgcggaggccctggagaggatgttcctgtccttccccaccaccaagacctacttcccgcacttcgacctgagccacggctctgcccaggttaagggccacggcaagaaggtggccgacgcgctgaccaacgccgtggcgcacgtggacgacatgcccaacgcgctgtccgccctgagcgacctgcacgcgcacaagcttcgggtggacccggtcaacttcaagctcctaagccactgcctgctggtgaccctggccgcccacctccccgccgagttcacccctgcggtgcacgcctccctggacaagttcctggcttctgtgagcaccgtgctgacctccaaataccgttaagctggagcctcggtggc 273 211798_x_attacgcagactccgtgaagggccgattcaccatctccagagacaattccaagaacacgctgtatcttcaaatgaacagcctgagagccgaggacacggccgtattactgtgcaagagagacttgtgtgattggggccaaggtaccctggtcaccgtgtcgagaggtggcggtggctcgggcggtggtgggtcgggtggcggcggatcttctgagctgactcaggaccctgctgtgtctgtggccttgggacagacagtcaggatcacatgccaaggagacagcctcagaagctattatgcaagctggtaccagcagaagccaggacaggcccctgtacttgtcatctatggtaaaaacaaccggccctcagggatcccagaccgattctctggctccagctcaggaaacacagcttccttgaccatcactggggctcaggcggaagatgaggctgactattactgtaactcccgggacagcagtggtaaccatgtggtattcggcggagggaccaagctgaccgtcctaggtgcggccgcagaacaaaaactcatctcagaagaggatctgaatggggccgcat 274211813_x_atttgcacaagtttcctgggctggaccgtttcaacagagaggcttatttgactttatgctagaagatgaggcttctgggataggcccagaagttcctgatgaccgcgacttcgagccctccctaggcccagtgtgccccttccgctgtcaatgccatcttcgagtggtccagtgttctgatttgggtctggacaaagtgccaaaggatcttccccctgacacaactctgctagacctgcaaaacaacaaaataaccgaaatcaaagatggagactttaagaacctgaagaaccttcacgttgtctaccttcataacaacaatatctctgtagttggatcaagtgacttctgcccacctggacacaacaccaaaaaggcttcttattcgggtgtgagtcttttcagcaacccggtccagtactgggagatacagccatccaccttcagatgtgtctacgtgcgctctgccattcaactcggaaacta 275 211848_s_attgtccatacagagtgtgcattccctggcaggggctcctgctcacagcctcgcttttaaccttctggaacctgccaaacagtgcccagaccaatattgatggtgtgccgttcaatgtcgcagaagggaaggaggtccttctagtagtccataatgagtcccagaatctttatggctacaactggtacaaagggcaaagggtgcatgccaactatcgaattataggatatgtaaaaaatataagtcaagaaaatgccccagggcccgcacacaacggtcgagagacaatataccccaatggaaccctgctgatccagaacgtcacccacaatgacgcaggaatctataccctacacgttataaaagaaaatcttgtgaatgaagaagtaaccagacaattctacgtattctatgagtcagtacaagcaagttcacctgacctctcagctgggaccgctgtcagcatcatgattggagtactggctgggatggctctgatatagc276 211889_x_attgcacagtactcctggcttatcaatggaacattccagcaaagcacacaagagctctttatccctaacatcactgtgaataatagtggatcctatacctgccacgccaataactcagtcactggctgcaacaggaccacagtcaagacgatcatagtcactgagagacagaatctcaccatgttgcccgggctggactcgaactcctgggctcaagcaatcctcccatctgtttcccaaagtgctgagattacagataatgctctaccacaagaaaatggcctctcacctggggccattgctggcattgtgattggagtagtggccctggttgctctgatagcagtagccctggcatgttttctgcatttcgggaagaccggcagggcaagcgaccagcgtgatctcacagagcacaaaccctcagtgtccaaccacactcaggaccactccaatgacccacctaacaagatgaatgaagttacttattctaccctgaactttgaagccca277 211896_s_attcctccttcccttacggaattacatcttgatggcaacaaaatcagcagagttgatgcagctagcctgaaaggactgaataatttggctaagttgggattgagtttcaacagcatctctgctgttgacaatggctctctggccaacacgcctcatctgagggagcttcacttggacaacaacaagcttaccagagtacctggtgggctggcagagcataagtacatccaggttgtctaccttcat 278 211959_attcacaccgtagcccacatggatagcacagttgtcagacaagattccttcagattccgagttgcctaccggttgttttcgttgttgttgttgttgtttttctttttctttttttttgaagacagcaataaccacagtacatattactgtagttctctatagttttacatacattcataccataactctgttctctcc279 211964_atcactttccaatgccacagacaactcacattgttcaactcccnttctcggggtgggacagacgagacaacagcacacaggcagccagccgtggnnccagaggctcganggggctcaggggcntcanggcacccgtccccacacgnagggccccgtngggtgggncctnggccctngctttctacngccnaatgnttatgnccagctccatgttctcccaaataccgttgatgtgaattattttaaaggcaaaacngtgctctttattttanaaaacactgataatcacactgcggtaggtcattcttttgccacatccctatagaccactgggtttggcaaaactcaggcagaagtggaganccnttctagacatcantgtcagccttgctacttgaaggtacaccccatagggtcggaggtgctgtcccc 280 211985_s_atgaggcaaatggatctcgatatttcagatgggcttttgatgcactgttgccaaggaaggctttttctgattttttgacaaatgaatttttgcacactttcattggtgtctttcggcaacttacacacattgaaaat 281 211990_atgaggacttaggagagatctgaactccagctgccctacaaactccntcncagcttttcttctcacttcatgtgaaaactactccagtggctgactgaattgctgacccttcaagctctgtccttatccattacctcaaagcagtcattccttagtaaagtttccaacaaatagaaattaatgacactttggtagcactaatatggagattatcctttcattgagccttttatcctctgttctcctttgaagaacccctcac 282 211991_s_atgcactgggaggcccaagagccaatccagatgcctgagacaacggagactgtgctctgtgccctgggcctggtgctgggcctagtnggcatcatcgtgggcaccgtcctcatcataaagtctctgcgttctg 283 212077_attgcagaagtcaaaccctcatgacaaagtaggcacaagtctacaataagctaaatcagaatttacaaatacaagtgtcccaggtagcattgactcccgtcattggagtgaaatggatcaaagtttgaattaaggcctatggtaaggtaacattgctttgttgtacttttgaacaagagctcctcctgatcactattacatatttttctagaaaatctaaagttcagaagagaatgtatcactgctgacttttattccaatatttggatggagtaagttttagggtagaattttgttcagtttggatttaatcttttgaaaagtaaattccttgtttactggtttgactataattctctgttatctttacgaggtaaaactgcaagctgactagcatgttctgtgaatctgccattcctaaaaattttataaacacttgatacttttcactgataatggatcgctcca 284 212091_s_attcacagcgggcaggacggaccccgcccacgacgtgcgggtggcggtggtgcagtacagcggcacgggccagcagcgcccagagcgggcgtcgctgcagttcctgcagaactacacggccctggccagtgccgtcgatgccatggactttatcaacgacgccaccgacgtcaacgatgccctgggctatgtgacccgcttctaccgcgaggcctcgtccggcgctgccaagaagaggctgctgctcttctcagatggcaactcgcagggcgccacgcccgctgccatcgagaaggccgtgcaggnagnccagcgggcaggcatcgagatcttcgtggtggtcgtgggccgccaggtgaatgagccccacatccgcgtcctggtcaccggcaagacggccgagtacgacgtggcctacggcgagagccacctgttccgtgtccccagctaccaggccctgctccgcggtgtcttccaccagacagtctccaggaaggt285 212097_atgaatttcacctgtaaacctgagtcgtacagaaagctgcctggtatatccaaaangctttttattcctcctgctcatattgtgattctgccntttggggnacttttncttnaaaccttcagttatgatttttttttncatacacttattggnaactctgcttgatttttgcctcttccagtcttcctgacactttaattaccaacctgttactttgactttttgcatttaaaacagacactggcatggatatagttttacttttaaactgtgtacataactgaaaatgtgctatactgcatactttttaaatgtaaagatatttttatctttatatgaagaaaatcacttaggaaatggctttgtgattcaatctgtaaactgtgtattccaagacatgtctgttctacatagatgcttagtccctcatgcaaatcaattactggtccaaaagattgctgaaattttatatgcttactgatatattttacaattttttatcatgcatgtcctgtaaaggttacaagcctgcacaataa286 212136_attcttccccttgagcttcagagaggagagttggcatggttaaatctgaatggttacctcactgctgaaaacccagaggggcgtggcacactcgcttgtgtggaaaagcctctaaatgcatcccttcctttctttcctgcttcctttgccttacaattgaagcagcccgtggtaccatcacagtatgcagagacttcctcacctttcatatctagggaccacccccgatgcattggtgagggtgggcacttataaatgcctgctattgttaagccattccagcctcttcctctgaatagaccagacgccctttcacttagttcagtgccagtccttttgccttcccaaccctgctgttaggcctgctgttccctttgctcttgattaggagagatggaaggagatgagctcccataactgaattggcctttggttcatgttttctccccatatgtatatatgccatatgtgaatatgccatatatatgtgccaacaaatctatctacgttgttcttttcaaattagcacgcagataggaattttgagtttctcttctt 287 212158_attatgtaaactttaacttccactttgtataaatttttaagtgtcagactatccattttacacttgctttatttttcattacctgtagctttgggcagatttgcaacagcaaattaatgtgtaaaattggattattactacaaaaccgtttagtcatatctatctaatcagatcttcttttgggaggatttgatgtaagttactgacaagcctcagcaaacccaaagatgttaacagtattttaagaagttgctgcagattcctttggccactgtatttgttaatttcttgcaatttgaaggtacgagtagaggtttaaagaaaaatcagtttttgttcttaaaaatgcatttaagttgtaaacgtctttttaagcctttgaagtgcctctgattctatgtaacttgttgcagactggtg288 212185_x_atcgccggctcctgcaaatgcaaagagtgcaaatgcacctcctgcaagaaaagctgctgctcctgctgccctgtgggctgtgccaagtgtgcccagggctgcatctgcaaaggggcgtcggacaagtgcagctgctgcgcctgatgctgggacagccccgctcccagatgtaaagaacgcgacttccacaaacctggattt289 212192_atcaactgtttttgcgactttataggcaggtaaattttgctattactattgaatacaaatgacaattcatttatgaccactcaaacagcgttagtaaccatttagtgacaaaggattaaaacatccatctggatgttaattttgaagatgtaaattatatgttgtttaaatttttccaggcatctgaaaaccttatctgctagacaatgtaagattcacacagagttatctgggattctgattttttaaatagtacatatcattaaaccattttctctaaatgtaagaagagcagaaaaaatcttataagattatcagatttttctaatgacacagaaatgtaagaaaaaaatccctttatattgaaaaaagatgcagtcaaagtcttttcagacatgcccaaactttgaagaatttcttcaaccatctaatgctataaagatttttgttcttcctgttcacaaccagttgtataacagaaatactagctactgttttccttc 290 212195_atgatgggtcgtgtgatgagatgcatttaaggccgatagtgatagatgttttttttatttcttgaacacaggctttgtctgaatgatgttcttttatctcttgaacacaagctttgaatgataactacaggttttaagtgctgttacattaataccataatgtgatgtgttagaaacaaagggatatttcaaaggtagatatttgaaaattctctagtctcaatatgtatgtgtattgaatatactctaaaaataaatgtgcaatttgctagtaggacaatgcagtgactgactagcattaggtatgtttcttttatatcctagctatgtcccactttcttctaagtgcaatcctttcatgttcacttgctgttttaccccatctactctaacttcatttggaaggcttgtctagagtatagcatgtatttttacctttgcagtgaattgcatgtgctaattgtaaccacagctatttttatgttgacataactccaaatgttatattaaatgttctattatatattagctctaatcccttaagtaaa291 212224_atacagtgttctctaatgttacagatgagatgcgcattgccaaagaggagatttttggaccagtgcagcaaatcatgaagtttaaatctttagatgacgtgatcaaaagagcaaacaatactttctatggcttatcagcaggagtgtttaccaaagacattgataaagccataacaatctcctctgctctgcaggcaggaacagtgtgggtgaattgctatggcgtggtaagtgcccagtgcccctttggntgggattcaagatgtctggaaatggaagagaactgggagagtacggtttccatgaatatacagaggtcaaaacagtcacagtgaaaatctctcagaagaactcataaagaaaatacaagagtggagagaagctcttcaatagctaagcatctccttacagtcactaatat292 212230_atcaaggtcccactctaggtgatagacagggaccccttctactgaacctttgaggaaaggaggaaggaagaaatgcgtttagatcttggatgcagacctttcaaagggttaaatgtaaccatatggatcaaccacatgcacatccttactacagaatccgtcctttcatttcaacttatagcaagctatgatttttatatataaatattatataaataatgtataaaacattaaaagttaactatgtaagatattatttctgaaacaatttagctatatccactatgattataaactgtgtctcgacctgtgttatttacattagctgcttaaaaaagcattgagttaatttttttaaatatcaactaaaatatcatagttctgtggtagacattgttttataatgaaataactgcaactagagaaaactgtataaaaacattaaattgtcagtatttttgtaaggttccattttgtaaagagaataatattcaaagacttttgtagcatacaaagtgaaaacttgtatctgcgaaacta293 212233_ataagcagcctagggatgagcatttctttgaaagcaattaggttattcacctggtattaaaactatttactgttaaaaaatctgtgacttcatgaagttgatttttaaaggcagcatcaaaaactgaaaaggnaagggaaaaaataggcagcttctctgcacttgtttggagctccccaaaacaggagccatggagaagtggcatcaagaccgggctgccctttcgagaacaccctgtggcagttcagagacacgcttttcctacactgcatgcagcccctctttccagcactggaaagaagtggtcttgagcccagctgagaagcacttcacactcctctctcttgttctgaatggtgtttgtgtcagtctgcagctgtgtatggtattatgtcttataatcctgcatcacttctatcctatccagtcatat294 212265_atgggtagatgggagtgtcgcttgtatgttatcgtacagctgacatgtatttttgtctattctttattatcttagtttcatgctatgtatgtaccataaccaacctattgcctatgagaaacatgtaagataatgtatttacagccattgttacaagtttataatgtatttttctatcttgttttatatgtatgttatataacattcaaaaagaatttttttcttgattgagaaaaggatacaaaatgcaaaatccacaattttgataactgaaaattgccaattgttttgcagtactttattatattgggtgtcttgtcttttttgggcttttagttagctaatgaatgaatacattagacacttttgggttttagttgggattttacatagcttgcattttaattctttggttctttgctgtttctattaacccacagcattatt295 212288_atgaaggttgtcatgggctgttccttgggggtttttatcctgctcaccgtggagataagcctgcggcttgtctaaccagcgcagcgcaaaggtctcaatgccttttggtaacatccgtcattgcagaagaaagtttacacgacgtcaaaaagtgacgttcatgctaagtgtttttccagaaatattggtttcatgtttcttattggctctgcctcctgtgcttatatcatccaaaaactttttaaaaaggtccagaattctattttaacctgatgttgagcacctttaaaacgttcgtatgtgtgttgcactaattctaaactttggaggcattttgctgtgtgaggccgatcgccactgtaaaggtcctagagttgcctgtttgtctctggagat 296 212386_atgagatttaccatgtatcagtgcctggctttttgttataaagctttgtttgtctagtgctcttttgctataaaatagactgtagtacaccctagtaggaaaaaaaaaaaactaaatttaaaaataaaaaatatatttggcttatttttcgcaggagcaatccttttataccatgaatatt 297212387_atgtttatacaactgtcagtccacccagtggtgcaactggttctgattcagtcttccgatncctttttatttttcactttttcctatttctgaattttttttttnatttgtgatcttgattttgatgaggggttggggagtggggagggagtcgaaccaagacttggagttaagaggattttcatcttttgcatccaacaggcagaatatgatctgtgtccaaaagtgaacttgagtcaggaatgaatcaatttcagcataaacaagcacaaaaatttagtctgctggctgactggaagcaaaaaagtcaagatggaatatgatgaattccaacacaatggggcaccaaggcctttaggcctctctttttattttgctttggttttgtttgtttttctttagagacatgctctttctcatgggacttgaagtggactcatctttgtgcagtgctggttttgccatactcatttcaagtattatagacatatgtaatggtgaaaatatatgaactgtggcctttttcattcttgttacttgtg298 212397_atgaagtgactgttgtaccatggttgtgcacatgcttcagaatcctatggaagagaatattcctacttgcagtacatcaaaggaatggatggtggaccctactattcatgttttgagacataaatgttcactttaaagcaattgcataatagataaaaacctgaactttcattggatttttgttaattttcctcattttgaattatgtgcactaccatagctacatcagtttgatacagtattgaaaaattatcagttatattttgctgtttatgatctatttgtagattaggattaaaatggatttaatccatttttaaggctgtgtgaatttttctaaacaagaaccatttgcaatatggatttcttagagattaaaccaattataacttattagcagtcgcgagcacatgttcatatagtcaatgtaaaaatacactaatgagtatttggtaaatcccagtaggcttttaccattagca 299 212414_s_attccctcacttctcttaagccaagaagtttgctttccctagctgcagtgtagatggctcttgtttttgtttttttgttttaatcatttggcattcacatgtggctgttaatatgtgcttgttttt 300 212419_attggtgggagggctctcaatcagcagggccccaggagggaagaagaagtggggcaaagcntggcctcgccgctcgggagctttgccatctgagccacgcctcctccaggccatgctccttgaacttggaaatgtcaaccggagcccttacaccagccctccagcatctaatagacttgaatctactctaaacgaatatttaatccaacctcactacattgtagctcagtccaacgactaaccctgaaatgggggtgttccagccttcagcgagatggccaagcggtcccctgggggctgtggcagcggncttatccttctctgttgccaaccttgccgtccgacctcctccgcccccatgcggtgaccccgtccgtgtctgtgtctgtccatacgtgtgagtccagctaaaaagacaaaacagaacccgtgggcccagctcggaaggtgcgtggagaaggctccgacgtctccgaagtgcagcccttgggatggcattccgttgtgtgccttattcctggagaatctgtatacggctcgcctatagaa 301 212464_s_atcttctccaagcatcaccctgggagtttcctgagggttttctcataaatgagggctgcacattgcctgttctgcttcgaagtattcaatanccgctcagtattttaaatgaagtgattctaagantttggtttgggatcaatanggaaagncatatgnncagnnccaanccaagatgcaaatgttttgaaatgatatgaccaaaattttaagtaggaaagtcancccaaacacttctgctttcacttaagtgtctggcccgcaatactgtaggaacaagcatgatcttgttactgtgatattttaaatatccacagtactcactttttccaaatgatcctagtaattgcct 302 212592_atgtatcaaaatcttccaattatcatgctcacctgaaagaggtatgctctcttaggaatacagtttctagcattaaacaaataaacaaggggagaaaataaaactcaaggagtgaaaatcaggaggtgtaataaaatgttcctcgcattcccccccgcntttttttttttttttgactttgccttggagagccagagcttccgcattttctttactattctttttaaaaaaagtttcactgtgtagagaacatatatgcataaacataggtcaattatatgtctccattagaaaaataataattggaaaacatgttctagaactagttacaaaaataatttaaggtgaaatctctaatatttataaaagtagcaaaataaatgcataattaaaatatatttggacataacagactt303 212667_atcaggaggacacagcattattctagtgctgtactgttccgtacggcagccactacccacatgtaactttttaagatttaaatttaaattagttaacattcaaaacgcagctccccaatcacactagcaacatttcaagtgcttgagagccatgcatgattagtggttaccctattgaataggtcagaagtagaatcttttcatcatcacagaaagttctattggacagtgctcttctagatcatcataagactacagagcacttttcaaagctcatgcatgttcatcatgttagtgtcgtattttgagctggggttttgagactncccttagagatagagaaacagacccaagaaatgtgctcaattgcaatgggccacatacctagatctccagatgtcatttcccctctcttattttaagttatg304 212671_s_ataccaatgaggttcctgaggtcacagtgttttccaagtctcccgtgacactgggtcagcccaacaccctcatctgtcttgtggacaacatctttcctcctgtggtcaacatcacntggctgagcaatgggcactcagtcacagaaggtgtttctgagaccagcttcctctccaaagagtgatcattccttcttcaagatcagttacctcaccttcctcccttctgntgatgagatttatgactgcaaggtggagcactggggcctggatgagcctcttctgaaacactgggagcctg305 212713_atcacatggttctagcctggacctggctgggctccatgagaatgagttgcctccaccctgtcccaacagctgacagccaggagccactctcccagctgcaggcctttgtggtccatcttgtcctgcttcctcactgtggacccctgtctgggccaccctagtgtgctaagctgagcagtgcagtgtgaacagggcccatggtgtattctaggccacagcccagcactcctctgggctgctctcaaaccatgtcccatcttcagcatccctcccaccaacttactcccctgtggtgagtaccgtggaaccccagcccacctcactatcatactcagcttcccctgatggcccatcccagcccctgaagctntatgccaagaacacagctaccgcacaccaccctgaaacagccacagccaaggtaggcatgcatatgaggtcttccccataccctctgggtgttgagaggtttagccacatgagggagcagaggacaatctctgcagggctgggagtgggtagggactgaaggtctcaat 306 212730_attcagtgtctgggctcatgacttgtaaatggaagctgatgtgaacaggtaattaatattatgacccacttctatttactttgggaaatatcttggatcttaattatcatctgcaagtttcaagaagtattctgccaaaagtatttacaagtatggactcatgagctattgttggttgctaaatgtgaatcacgcgggagtgagtgtgcccttcacactgtgacattgtgacattgtgacaagctccatgtcctttaaaatcagtcactctgcacacaagagaaatcaacttcgtggttggatggggccggaacacaaccagtctttttgtatttattgttactgagacaaaacagtactcactgagtgtttttcagtttcctactggtggttttgatattgtttgtttaagatgtatatttagaatgacatcatctaagaagctgattttgctaaactcctgttccc 307 212741_atgaactcatgtgatttacccttttcaactttttggaaaacgatttaatttattctaattagattaaccctattaatctatggattgggtatcaaaatgaatgccagtccagatgtgcctagacacgaaattggagctgaggactctcacgatatgcaagttcatccaacgtgaagataccataagctttttctctgaaccagagaaatgaaagtcagtttaagaggctgatagatcttggccctgttaaggcatccacttcacagttctgaaggctgagtcagccccactccacagttaggccaagaattagattttaaaacttcatctgtctgtcccagttaactgttaaataaggcctcatcctccactgaagagtatggattgaaggattgtgaactatgtttagtgtgattgtgaacttggtgcctaatgttccatgtctgaagtttgccccagtgctacacgttggagta 308 212764_atgatgcaattggttctcctgcattgagatttgatttaacagtgttatgttaacatttatacttgccttggactgtagaacagaacttaaatgggaatgtattagttttacaactacaatcaagtcattttacctttacccagtttttaatataaaacttaaattttgaaattcactgtgtgactaatagcatgatgctctgcagttttattaagaaatnagcctaaccatacaactctcatttccttagtaagccaaattaggattaacttctataaacagtgttgggaacaatgtttaacattttgtgccaatttgttcctgtattcatgtatgtaagttacagatctgactcttcatttttaagttccttgttacatcatggtcatt 309 212814_atcctatcctacttgcccatatgagcacggctccccatggccacatactcctgcaaagcttttatgctgcttcgcttttctctaaacagatctgatattgctgctcctgtggttttctcaaaattaactttgccgtggtttttaaaaaggaatcaaaatgcattgttgcattaagctttttcaataaaggaaaattacggaaggaaaataggcaacaccagcaaattatatgtggacaggttctaaactctatatatacatatatatatatatatctatatatctatatacgtaatcatctagttctgtcatcttactgaaaggaataacacttctaaagatcaccatttctgagaagttcttggaaatctttatgtctaa 310 212859_x_atcaccgcgcagagctcagggggtggtgcgcccggcccttctgcggcgcacagcccagcccaggaacgcgggcggtgcggactcagcgggccgggtgcaggcgcggagctgggcctctgcgcccggcccganctccgtctataaanagagcagccagttgcagggctcnantctgctttccaactgcctgactgcttgttcgtctcactggtgtgagctccagcatcccctttgctcgaaatggaccccaactgctcttgcgccactggntggctcctgcacgtgcgccggctcctgcaagtgcaaagagtgcaaatgcacctcctgcaagaagagctgctgttcctgctnccccgtggnctgtgccaagtgtgcccagggctgcgtctgcaaaggggcatcggagaagtgcagctgctgtgcctgatgtgggaacagctcttctcccagatgtaaatagaacaacctgcacaacctggnatttttttaaaaatacaacactgagccatttgctgcatttc311 212956_attactgatgcttctgatactggatgtttagcttcttactgcaaaaacataagtaaaacagtcaactttaccatttccgtattctccatagattgaagaaatttataccacatatcgcatatgaccatctttccatcaaatcaatgtagagataatgtaaactgaaaaaaaatctgcaagataatgtaactgaatgttttaaaaacagaacttgtcactttatataaaagaatagtatgctctatttcctgaatggatgtggaaatgaaagctagcgcacctgcactttgaattcttgcttcttttttattactgttatgattttgctttttacagatgttggacgattttttcttctgattgttgaattcataatcatggtctcatttcctttgcttctttggaatatttctttcaacacattcctttattttattatacattgtgtcctttttttagctattgctgct 312 213068_atgacaggagggtgtccacatatgttaacatcagttggatctcctatagaagtttctgctgctctttccttctccctgagctggtaactgcaatgccaacttcctgggcctttctgactagtatcacacttctaataaaatccacaa 313 213071_atgctccacatgagccatgcatgcttagcaatccaagtgcagagctctttgctccaggagtgaggagactgggaggtgaaatggggaaatggaagggtttggaggcagagctgaaaacagggttggaaggatttcctgaattagaagacaaacgttagcatacccagtaaggaaaannngnnnaggggccanggggaacccgtgaggatcactctcaaatgagattaaaaacaaggaagcagagaatggtcagagaatgggattcagattgggaacttgtggggatgagagtgaccaggttgaactgggaagtggaaaaaggagtttgagtcactggcacctagaagcctgcccacgattcctaggaaggctggcagacaccctggaaccctggggagctactggcaaactctcctggattggncctnatnnttttggtgggaaaggctgccctggggatcaactttccttctgtgtgtggctcaggagttcttctgcagagatggcgctatctttcctcctcctgtgatgtcctgctcccaaccatttgtactcttcatta 314 213317_ataagtgtgcataatttcatttaacgttaaagaaatagatccaattcctttcttgcaaccaaaaataaataaaatacgttgcctcaatataaggtttgggctattctgtgtttctatagaagcaatctgtttttggtaaaatgtacttttaaggatccagtcatctgaagtattttatgtagagttagagatttcacaatattgactatacatatatttaaaatataaattatccagctgatgtttgaatttgtcttactttcctggccacctcgttgtcctattttataagctggggagttaactagcttaacaaaagatgcttagcttttgtaaaagaacaagtgtttcattttacaaagacactccaaatgatagttacttgattttctcgagacctttaactatggtgatgaataacaggacttgctttcaagccttaataaatgtaaaatgccttttaatgaagatacagctgagtgttttcctcatgaatctgaaccaattaccaatttgtgttccagtcttgatt315 213428_s_atgaaaccaaggtcaggaggccgttgcagacataaatctcggcgactcggccccgtctcctgagggtcctgctggtgaccggcctggaccttggccctacagccctggaggccgctgctgaccagcactgaccccgacctcagagagtactcgcaggggcgctggctgcactcaagaccctcgagattaacggtgctaaccccgtctgctcctccctcccgcagagactggggcctggactggacatgagagccccttggtgccacagagggctgtgtcttactagaaacaacgcaaacctctccttcctcagaatagtgatgtgttcgacgttttatcaaaggccccctttctatgttcatgttagttttgctccttctgtgtttttttctgaaccatatccatgttgctgacttttc316 213451_x_atcacaggcaggtgactactccatgcgcgtggacctgcgggctggggacgaggctgtgttcgcccagtacgactccttccacgtagactcggctgcggagtactaccgcctccacttggagggctaccacggcaccgcaggggactccatgagctaccacagcggcagtgtcttctctgcccgtgatcgggaccccaacagcttgctcatctcctgcgctgtctcctaccgaggggcctggtggtacaggaactgccactacgccaacctcaacgggctctacgggagcacagtggaccatcagggagtgagctggtaccactggaagggcttcgagttctcggtgcccttcacggaaatgaagctgagaccaagaaactttcgctccccagcggggggaggctgagctgctgcccacctctctcgcaccccagtatgactgccgagcactgaggggtcgccccgagagaagagccagggtccttcaccacccagccgctggaggaagccttctctgccagcgatctcgcagcactgtgtttacag 317 213509_x_atccaatggcgagggtctgccacactggccgctgttcgaccaggaggagcaatacctgcagctgaacctacagcctgcggtgggccgggctctgaaggcccacaggctccagttctggaagaaggcgctgccccaaaagatccaggagctcgaggagcctgaagagagacacacagagctgtagctccctgtgccggggaggagggggtgggttcgctgacaggcgagggtcagcctgctgtgcccacacacacccactaaggagaaagaagttgattccttcattcacttcgccattcattcatacttccgtccatccattcagaaagcatttattaagaatttactcaggcatgatggcccatacttgtaatcccagctattgggaaggatgagatgggaggatggcttgaggccagaggtttgagaccgaccagcc 318 213624_atgggagagtccatctggaagctggagtatatcctgacccagacctacgacattgaagatttgcagccggaaagtttatatggattagctaaacaatttacaatcctagacagtaagcagtttataaaatactacaattacttctttgtgagttatgacagcagtgtaacatgtgataagacatgtaaggcctttcagatttgtgcaattatgaatcttgataatatttcctatgcagattgcctcaaacagctttatataaagcacaattactagtatttcacagtttttgctaatagaaaatgctgattctgattctgagatcaatttgtgggaattttacataaatctttgttaattactgagtgggcaagtagacttcctgtctttgctttctttttttttttctttttgatgccttaatgtagatatctttatcattctgaattgtattatatatttaaantgctcattaatagaatgatggatgtaaattggatgtaaatattcagtttatataattatatctaatttgtacccttgttgaaattgtcattta319 213629_x_atcttcgcttctctcttggaaagtccagtctctcctcggcttgcaatggaccccaactgctcctgcgccgctggtgtctcctgcacctgcgctggttcctgcaagtgcaaagagtgcaaatgcacctcctgcaagaagagctgctgctcctngctnccccgtgggctgtagcaagtgtgcccagggctgtgtttgcaaaggggcgtcagagaagtgcagctgctgcgactgatgccaggacaacctttctcccagatgtaaacagagagacatgtacaaacctggattttttttttataccaccttgacccatttgctacattccttttcctgtgaaa 320 213746_s_atcctggggctgagcaaggcctacgtaggccagaagagcagcttcacagtagactgcagcaaagcaggcaacaacatgctgctggtnggggttcatggcccnangaccccctgcgaggagnnnnngnngnagcacgtgggcagccggctntacagcgtgtcctacctgctcaaggacaagggggagtacacactggtggtcaaatggggg 321 213891_s_atgaaactgtatgggtagcttttttgtttgttttttgttttgtttttgtttttgtttttgtttttagttgtaggtcgcagcggggaaattttttgcgactgtacacatagctgcagcattaaaaacttaaaaaaattgttaaaaaaanaaaaaaagggaaaacatttcaaaaaaaaaaaaanngataaacagttacaccttgttttcaatgtgtggctgagtgcctcgattttttcatgtttttggtgtatttctgatttgtagaagtgtccaaacaggttgtgtgctggagttccttcaagacaaaaacaaacccagcttggtcaaggccattacctgtttcccatctgtagttattcg 322 213921_atgctgctgccgcggggaagcaggaactggccaagtacttcttggcagagctgctgtctgaacccaaccagacggagaatgatgccctggaacctgaagatctgtcccaggctgctgagcaggatgaaatgaggcttgagctgcagagatctgctaactcaaacccggctatggcaccccgagaacgcaaagctggctgcaagaatttcttctggaagactttcacatcctgttagctttcttaactagtattgtccatatcagacctctgatccctcgcccccacaccccatctctcttccctaatcctccaagtcttcagcgagacccttgcattagaaactga 323 213953_atacaggaaattgctacttaccgccgccttctggaaggagaagacgtaaaaactacagaatatcagttaagcaccctggaagagagagatataaagaaaaccagnaagattaagacagtcgtgcaagaagtagtggatggcaaggtcgtgtcatctgaagtcaaagaggtggaagaaaatatctaaatagctaccagaaggagatgctgctgaggttttgaaagaaatttggctataatcttatctttgctccctgcaagaaatcagccataagaaagcactattaatactctgcagtgattagaaggggtggggtggcgggaatcctatttatcagactctgtaattgaatataaatgttttactcagaggagctgcaaattgcctgcaaaaatgaaatccagtgagcactagaatatttaaaacatcattactgccatctttatcatgaagcacatcaattacaagctgtagaccacctaatatca 324214027_x_atgagaaagccaggcaggtagccagggggactagcccctgtggagactggggggcttgaaattgtccccgtggtctcttactttcctttccccagcccagggtggacttagaaagcaggggctacaagagggaatccccgaaggtgctggaggtgggagcaggagattgagaaggagagaaagtgggtgagatgctggagaagagaggagaggagagaggcagagagcggtctcaggctggtgggaggggcgcccacctccccacgccctcccctcccctgctgcaggggctctggagaga325 214038_atatgagccttcatacatggactgagagtcagagcttgaagaaaagcttatttattttccccaacctcccccaggtgcagtgtgacattattttattataacatccacaaagagattatttttaaataatttaaagcataatatttcttaaaaagtatttaattatatttaagttgttgatgttttaactctatctgtcatacatcctagtgaatgtaaaatgcaaaatcctggtgatgtgttttttgtttttgttttcctgtgagctcaactaagttcacggcaaaatgtcattgttctccctcctacctgtctgtagtgttgtggggtcctcccatggatcatcaaggtgaaacactttggtattctttggcaatcagtgctcctgtaagtcaaatgtgtgctttgtactgctgttgtt326 214091_s_atatgcctacaggtatgcgtgattgtgtgtgtgtgcatgggtgnacagccacntgtctacctatgtgtctttctgggaatgtgtaccatctgtgtgcctgcagctgtgtagtgctggacagtgacaaccctttctccagttctccactccaatgataatagttcacttacacctaaacccaaaggaaaaaccagctntaggtccaattgttntgctctanactgatacctcaaccttggggccagcatctcccactgcctccaaatattagtaantatgactgacgtncccanaagtttntgggtnnnaccacactccccaaccccccactcctanttcctgaagggccctcccaaggntacatccccaccccacagttctccctgagagagatcaacctccctgagatcaaccaaggcagatgtgacagcaagggccacggacc 327 214142_atgcctctggcaatgccattcaggccaggtcttcctcctatngtgnagannatnnnnntggnggtggaaagcgattctctcattctggcaaccagttggnacggccccatcaccgccctccgggtccgagtcaacacatactacatcgtaggtcttcaggtgcgctatggcaaggtgtggagcgactatgtgggtggtcgcaacggagacctggaggagatctttctgcaccctggggaatcagtgatccaggtttctgggaagtacaagtggtacctgaagaagctggtatttgtgacagacaagggccgctatctgtcttttgggaaagacagtggcacaagtttcaatgccgtccccttgcaccccaacaccgtgctccgcttcatcagtggccggtctggttctctcatcgatgccattggcctgcactgggatgtttaccccactagctgcagcagatgctgagcctcctctccttggcaggggcactgtgatgaggagtaagaactcccttatcactaac328 214164_x_atacaaggcccaggctggggccagggccagaggggaaggccctggattctcactcatgtgagatcttgaatctctttctttgttctgtttgtttagttagtatcatctggtaaaatagttaaaaaacaacaaaaaactctgtatctgtttctagcatgtgctgcattgactctattaatcacatttcaaattcaccctacattcctctcctcttcactagcctctctgaaggtgtcctggccagccctggagaagcactggtgtctgcagcacccctcagttcctgtgcctcagcccacaggccactgtgataatggtctgtttagcacttctgtat 329 214414_x_attcaacttcaagctcctaagccactgcctgctggtgaccctggccgcccacctccccgccgagttcaacccctgnggtgcacgcctccctgganaagttcctggcttctgtgagcaccgtgctgacctccaaataccgttaagctggagcctcggtagccgttcnnnnnncnngctnggcnntccaacgggccctcctcccctccttgcaccggcccttcctggtctttgaataaagtctgagtg 330 214433_s_atcttcctcggaggcagcattgttaagggaggccctgtgcaagtgctggaggacgaggaactaaagtcccagccagagcccctagtggtcaagggaaaacgggtggctggaggccctcagatgatccagctcagcctggatgggaagcgcctctacatcaccacgtcgctgtacagtgcctgggacaagcagttttaccctgatctcatcagggaaggctctgtgatgctgcaggttgatgtagacacagtaaaaggagggctgaagttgaaccccaacttcctggtggacttcgggaaggagccccttggcccagcccttgcccnatgagctccgctaccctgggggcgattgtagctctgacatctggatttgaaggctccaccctcatcacccacactccctattttgggccctcacttccttggggacctggcttcattctgctctctcttggcacccgacccttggcagcatgtaccacacagccaagctgagactgtggcaatgtgttgagtcatatacatttactgaccactgttgct 331 214505_s_atccatcggtgcggactccaaggaggtgcactataagaaccgcttctggcatgacacctgcttccgctgtgccaagtgccttcaccccttggccaatgagacctttgtggccaaggacaacaagatcctgtgcaacaagtgcaccactcgggaggactcccccaagtgcaaggggtgcttcaaggccattgtggcaggagatcaaaacgtggagtacaaggggaccgtctggcacaaagactgcttcacctgtagtaactgcaagcaagtcatcgggactggaagcttcttccctaaaggggaggacttctactgcgtgacttgccatgagaccaagtttgccaagcattgcgtgaagtgcaacaagggtttggtaaaggctccagtgtggtggcctatgaaggacaatcctggcacgactactgcttccactgcaaaaaatgctccgtgaatctggccaacaagcgctttgttttccaccaggagcaagtgtattgtcccgactgtgc332 214598_atttgtcaaggggctttgcattcaaactgcttttccagggctatactcagaagaaagataaaagtgtgatctaagaaaaagtgatggttttaggaaagtgaaaatatttttgtttttgtatttgaagaagaatgatgcattttgacaagaaatcatatatgtatggatatattttaataagtatttgagtacagactttgaggtttcatcaatataaataaaagagcagaaaaatatgtcttggttttcatttgcttaccaaaaaaacaacaacaaaaaaagttgtcctttgagaacttcacctgctcctatgtgggtacctgagtcaaaattgtcatttttgttctgtgaaaaataaatttccttcttgtaccatttctgtttagttttactaaaatctgtaaatactgtatttttctgtttattccaaatttgatgaaactgacaatccaatttgaaagtttgtgtcgacgtctgtctagcttaaatgaatg 333 214677_x_attcataagtgacttctacccgggagccgtgacagtggcctggaaggcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaaagcaacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcccacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcccctacagaatgttcataggttctcaaccctcac 334 214696_atgagtatacatcggtgcaggcttcctggatgacagttgggtgatatgtgtcatgtggcctaaaagcctccatgtcatttgacctacgaattctatctttgggaatttatcctaagaaantacttanggatttanttngtgataagatgttcatcccagcattgcaatggagaaaaatgggaagcaatggtttggttgggaatttattccttttctgctgtaacgaaagtttgcaataggggattgcttaagtaaattattgtatctccatccagatggtggagtaccgcgcagacattaaaagtcatgtaaaagaacatctgactgaaagaaaaatgctccttgaatattaaaaggttgtaaaaatagtgcatgttatgtgatttcaattttgttttttaaaatatgggtgtatgcttgtatacgtagagcagataaaaaagacggaaggcatactaaaaaatgttgagtggttatctttgtatggtggaacaaagtcactgtaattttcatctttggtt335 214752_x_attggggctgagcaaggcctacgtaggccagaagagcagcttcacagtagactgcagcaaagcaggcaacaacatgctgctggtgggggttcatggcccaaggaccccctgcgaggagatcctggtgaagcacgtgggcagccggctctacagcgtgtcctacctgctcaaggacaagggggagtacacactggtggtcaaatggggggacgagcacatcccaggcagcccctaccgcgttgtggtgccctgagtntggggcccgtgccagccggcagcccccaagcctgccccgctacccaagcagccccgccctnttcccctcaaccccggcccaggccgccctggccgcccgcctgtcactgcagccgcccctgccctgtgccgtgntgcgctcacctgcctccccagccagccgctgacctctcggctttcacttgggcagagggagccatttggtggcgctgcttgtcttctttggttctgggaggggt336 214768_x_ataatgctctgggtctctggatccagtggggnatattgtgatgactcagtctccactctccctgcccgtcacccctggagagccggcctccatctcctgcaggtctagtcagagcctcntgcatnntaatggatacaactatttggattggtacctgcagaagccagggcagtctccacagctcctgatctatttgggttctaatcgggcctccggggtcccngacaggttcagtggcagtggatcaggcacagattttacactgaaaatcagcagagtggaggctgaggatgttggggtttattactgcatgcaagctctacaaactcctcngacnttnggccangggaccaagntgganatcaaacgaactgtggctgcaccatct 337214777_atgcaagatggtgttgcagacccaggtcttcatttctctgttgctctggatctctggtgcctacggggacatcgtgatgacccagtctccagactccctggctgtgtctctgggcgagagggccaccatcaactgcangtccagccagagtgttttatacagctccaacaataagaactacttagcttggtaccagcagaaaccaggacagcctcctaagctnctcatttactgggcatctacccgggaatccggggtccctgaccgattcagtggcagcgggtctgggacagattt338 214916_x_atgaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtccctgagactctcctgtgcagcctctggattcacctttagcanctatgccatgagctgggtccgccaggctccaggnaaggggctggagtgggtctcanntattagtggtagtggtnntancacatactacgnagactccgtgaagggccggttcaccatctccagagacaattccaagaacacgctgtntctgcaaatgaacagcctgagagccgaggncacggccgtatattactgtncnnnagaaaatggtgtcagcagttgganntnccaaganannaccccaacctatgttgactactggggccaggaaccctggtcaccgtctcctcagggagtgcatccgccccaacccttttccccctcgtctcctgtgagaattccccgtcggatacgaagcagcgtggccgttggctgctc 339 215049_x_atcgtcagtcatcctttattgcagtcgggatccttggggttgttctgttggccattttcgtcgcattattcttcttgactaaaaagcgaagacagagacagcggcttgcagtttcctcaagaggagagaacttagtccaccaaattcaataccgggagatgaattcttgcctgaatgcagatgatctggacctaatgaattcctcagaaaattcccatgagtcagctgatttcagtgctgctgaactaatttctgtgtctaaatttcttcctatttctggaatggaaaaggaggccattctgagccacactgaaaaggaaaatgggaatttataacccagtgagttcagcctttaagataccttgatgaagacctggactattgaatggagcagaaattcacctctctcactgactattacagttgcatttttatggagttcttcttctcctaggattcctaagactgctgctga 340 215076_s_atggggaatggagcaaaacagtctttgaatatcgaacacgcaaggctgtgagactacctattgtagatattgcaccctatgacattggtggtcctgatcaagaatttggtgtggacgttggccct 341 215118_s_atcttgctctgttgcagattggcagatgccgcctccctatgtggtgctggacttgccgcaggagaccctggaggaggagacccccggcgccaacctgtggcccaccaccatcaccttcctcaccctcttcctgctgagcctgttctatagcacagcactgaccgtgaccagcgtccggggcccatctggcaacagggagggcccccagtactgagcgggagccggcaaggcacagggaggaagtgtggaggaacctcttggagaagccagctatgcttgccagaactcagcc342 215125_s_atgcataaattaatcagccccagagtgctttaannnnttctcttaaataccggtgtctttgatcaggatgacatgtgccatttttcagaggacgtgcagacaggctggcattctagattacttttcttactctgaaacatggcctgtttgggagtgcgggattcaaaggtggtcccaccgctgcccctactgcaaatggcagttntaatcttatcttttggcttctgcagatggttgcaatngatccttaaccaataatggtcagtcctcatctctgt 343 215176_x_atctactctggctccgaggtgccagatgtgacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggcaagtcagagcattagcagctatttaaattggtatcagcagaaaccaggnaaagcccctangctcctgatctatgctgcatccantttgcaaagtggggtcccatcaaggttcagtggcagtggatctgggacagatttcactctcaccatcagcagtctgcaacctgaagattttgcaacttactactgtcaacagagttacagtacccctca344 215193_x_atgccgagtactggaacagccagaaggacntcctggaagacnagcgggccnnggtggacacctactgcagacacaactacggggttgnngagagcttcacngtgcagcggcgagtccatcctnaggtgactgtgtatcctncaaagacccagcccctgcagcaccacaanctcctggtctgntctgtgagtggtttctatccaggcagcattgnaagtcaggtggttncggaanggcnaggaagagaagnctggggntggtgtccacnggcctgatccagaatggagactggaccttccagaccctggtgatgctngaaacagttcctcggagtggagaggtttacacctgccaagtggagcacccaagcntnacgagccctctcacagtggaatggagngcacggtctgaatctgcacagagcaagatgctgagtggagtcgggggctt 345 215299_x_ataagatcctggagtttgtggggcgctccctnccagaggagacngtggacntcatggttnagcacacgtcgttcaaggagatgaagaagaaccctatgaccaactacaccaccgtccnccnggagttcatggaccacagcatctcccccttcatgaggaaaggcatggctggggacnngngnngnccacnttcaccgtggcgcagaatgagcgcttcgatgcggacntatgcggagaagatggcaggncngcagcctcangcttccgctntgagcngtgagaggggnnncntggagtcacngcagagggagtgtgcgaatcaaacctgaccaagcggntcaagaataaaatatgaattgagggccngggacggtaggtcatgtctgtaatcccagcaatttggaggctgaggtgggaggatcatttgagcccaggagttcgagaccaacctgggcaacatagtgagattctgttaaaaaaataaaataaaataaaaccaatttttaaaaagagaataaaatatgattgtgggccaggcagagtggctcatgc 346 215382_x_atccggtcagcaggatcatcgtgcacccacagttctacatcatccagactggagcggatatcgccctgctggagctggaggagcccgtgaacatctccagccgcgtccacacggtcatgctgccccctgcctcggagaccttccccccgggnntgccgtgctgggtcactggctggggcgatgtggacaatgatgagcccctcccaccgccatttcccctgaagcaggtgaaggtccccataatggaaaaccacatttgtgacgcaaaataccaccttggcgcctacacgggagacgacgtccgcatcatccgtgacgacatgctgtgtgccgggaacacccggagngnntcatgccagggcgactcnggagggcccctggtgtgcaaggtgaatggcacctggctncaggcgggcgtggtcagctgggncgagggctgtgcccagcccaaccggcctggcatctacacccgtgtcacctactacttggactggatcc347 215388_s_atgaaccacctcaatgcaaagattctacgggaaaatgtgggccccctccacctattgacaatggggacattacttcattcccgttgtcagtatatgctccagcttcatcagttgagtaccaatgccagaacttgtatcaacttgagggtaacaagcgaataacatgtagaaatggacaatggtcagaaccaccaaaatgcttacatccgtgtgtaatatcccgagaaattatggaaaattataacatagcattaaggtggacagccaaacagaagctttatttgagaacaggtgaatcagctgaatttgtgtgtaaacggggatatcngtctttcatcacgttctcacacattgcgaacaacatgttgggatgggnnnctggagtatccaacttgtgcannnngatagaatcaatcataaaatgcacacctttattcagaactttagtattaaatcagttcttaatttcatttttaagtattgttttactcctttttattcatacgtaaaattttggatta348 215657_attcttccaatttattatctgcaccaattattttgggcacttctcctgtgtatgtaaactttggagtttaggtctacgtcatttatataagagcctgtagacctgagtggatggacactgcctcttagaactagaacttagaactttatcttgaaaatgtacnncnnnngcngaannnccncacagagtatgtgtcaggtaggaaccaaatttatgattgttatattcaaactggttttctgttccttgaaaatggtnttttttctgatcaaagcctatttaggagttattatgttcttgagtttattccatgtgtgtgaatattttgaatgaatccactaataagatatgcatgtatgtctggannnnnnncnnnnnagaataaatatttaagtagactttaacaagtaaatggttgtaggcatcattaagtcttaaatagccttttcaaagatattagtgttctngttttaattattcagataattcctttaattctccactcaaatctgacttta349 215867_x_atgattcctgtgggtccagctttggaactgggaaacctttcttcggatccgcactcattccactgatgccagctgcccctgaaggatgccagtactgtggtgtgtgagtctcagcagccgcccacacgctcctaactctgctgcatggcagatgcctaggtggaaatagcaaaaacaaggcccgggctggggccagggccagaggggaaggccctggattctcactcatgtgagatcttgaatctctttctttgttctgtttgtttagttagtatcatctggtaaaatagttaaaaaacaacaaaaaactctgtatctgtttctagcatgtgctgcattgactctattaatcacatttcaaattcaccctacattcctctcctcttcactagcctctctgaaggtgtcctggccagccctggagaagcactggtgtctgcagcacccctcagttcctgtgcctcagcccacaggccactgtgataatggtctgtttagcacttctgtat350 216207_x_atctctggctcccaggtgccagatgtgccatccagttgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggcaagtcagggcattagcagtgctttagcctgntatcagcagaaaccagggaaagctcctaagctcctgatctatgatgcctccagtttgnaaantggggtcccatcaaggttcagcggcagtggatctgggacagatttcactctcaccatcagcagcctgcagcctgaagattttgc 351216336_x_atccaactgcctgactgcttgttggcctcaccggtgggagctccagcatctcctttgctcgaaatggaccccaactgctcctgtgccactggtggctcctgcatgtgcgccggctcctgcaagtgcaaagagtgcaaatgcacctcctgcaagaagagctgctgctcctgctgccccgtgggctgtgccaagtgtgcccagggctgcatctgcaaaggggcgttggagaagtgcaactgctatgcctgacgtggggacagctctgctcccagatgtaaatagagtaacctgcacaaacctggattttttaaaaaatacaacactgagccatttgcttcatt 352 216401_x_attcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggtgagtcagggcattagcagttatttaaattggtatcggcagaaaccagggaaagttcctaagctcctgatctatagtgcatccaatttgcaatctggagtcccatctcggttcagtggcagtggatctgggacagatttcactctcactatcagcagcctgcagcctgaagatgttgcaacttattacggtcaacggacttacaatgccc 353 216442_x_attggaggaagttctccagcttcagctcaactcacagcttctccaagcatcaccctgggagtttcctgagggttttctcataaatgagggctgcacattgcctgttctgcttcgaagtattcaataccgctcagtattttaaatgaagtgattctaagatttggtttgggatcaataggaaagcatatgcagccaaccaagatgcaaatgttttgaaatgatatgaccaaaattttaagtaggaaagtcacccaaacacttctgctttcacttaagtgtctggcccgcaatactgtaggaacaagcatgatcttgttactgtgatattttaaatatccacagtactcactttttccaaatgatcctagtaattgcctagaaatatctttctcttacctgttatttatcaatttttcccagtatttttatacggaaaaaattgtattgaaaacacttagtatgcagttgataagaggaatttggtataattatggtgggtgattattttttatactgtatgtgccaaagctttactactgtg354 216474_x_atccgccatttcctctgaagcaggtgaaggtccccataatggaaaaccacatttgtgacgcaaaataccaccttggcgcctacacgggagacgacgtccgcatcgtccgtgacgacatgctgtgtgccgggaacacccggagggactcatgccagggcgactccggagggcccctggtgtgcaaggtgaatggcacctggctgcaggcgggcgtggtcagctggggcgagggctgtgcccagcccaaccggcctggcatctacacccgtgtcacctactacttggactggatccaccactatgtccccaaaaagccgtgagtcaggcctgggttggccacctgggtcactggaggaccaa 355 216491_x_atagtcgggcccaggactggtgaagccttcggagaccctgtccctcacctgcactgtctctggtggctccatcagtagttactactggagctggatccggcagcccgccgggaagggactggagtggattgggcgtatctataccagtgggagcaccaactacaacccctccctcaagagtcgagtcaccatgtcagtagacacgtccaagaaccagttctccctgaagctgagctctgtgaccgccgcggacacggccgtgtattactgtgcga 356216510_x_atagtgggtctcagctattagtgggagtgcaggtaccacatactacgcagactccgtgaagggccggttcaccacctccagagacaattccaagaacacgctgtatctgcaaatgnacagnctgagagccgaggacacggccgtatattactgtgcgaaatccc 357216576_x_attcctccctgtctgcatctgtaggagacagagtcaccatcacttgccaggcgagtcaggacattagtaattttttaacttggtatcagaagaagccagggaaagcccctaaagtcctgatctacgatgcatccaatttggaaacaggggtcccatcaaggttcagtggaagtggttctgggacagattttactttcaccatcgccagcctgcagcctgacgattttgcaacatattactgtcaacaatataatgatcaccccctcactttcggccctgggaccaaagtg358 216834_atatgaaactgattacaacaggctgtaagaatcaaagtcaactgacatctatgctacatattattatatagtttgtactgagctattgaagtcccattaacttaaagtatatgttttcaaattgccattgctactattgcttgtcggtgtattttattttattgtttttgactttggaagagatgaactgtgtatttaacttaagctattgctcttaaaaccagggatcagaatatatttgtaagttaaatcattggtgctaataataaatgtggattttgtattaaaatatatagaagcaatttctgtttacatgtccttgctacttttaaaaacttgcatttattcctcagatttt 359 216984_x_atcatctcctgcactggaaccagcagtgacgttggtgcttataactatgtctcctggtaccaacagcacccaggcaaagcccccaaactcatgatttatgaggtcagtaatcggccctcaggggtttctaatcgcttctctggctccaagtctggcaacacggcctccctgaccatctctgggctccaggctgacgacgagggtgattactactgcatctcatatacaagtagcaaccctctcgtggtt 360 217022_s_attcaagtgggaagagcgctgttcaaggaccacctgagcgtgacctctgtggctgctacagcgtgttccagtgtcctgccgggctgtgccgagccatggaaccatggggagaccttcacttgcactgctgcccaccccgagttgaagaccccactaaccgccaacatcacaaaatccggaaacacattccggcccgaggtccacctgctgccgccgccgtcggaggagctggccctgaacgagctggtgacgctgacgtgcctggcacgtggcttcagcccaaggatgtgctggttcgctggctgcaggggtcacaggagctgccccgcgagaagtacctgacttgggcatcccggcaggagcccagccagggcaccaccaccttcgctgtgaccagcatactgcgcgtggcagccgaggactggaagaagggggacaccttctcctgcatggtgggccacgaggccctgccgctggccttcacacagaagaccatcgaccgcttggcgggtaaacccacccatgtcaatgtgtctgttgtcatggcgga 361 217109_atgctgtcaggattcttcaaggagaatgaatactgggaatcaagacaggactataccttatccataggcgcaggtgcacagggggaggccataaagatcaaacatgcatggatgggtcctcacgcagacacacccacagaaggacactagcctggcgcgcgtgcacacacacacacacacacacgagttcataatgtggtgatggccctaagttaagcaaaatgcttctgcacacaaaactctctggtttacttcaaat 362 217110_s_atgcacctgagcatgaaactcgacgcgttcttcggcatcttctttggggccctgggcggcctcttgctgctgggggtcgggacgttcgtggtcctgcgcttctggggttgctccggggccaggttctcctatttcctgaactcagctgaggccttgccttgaaggggcagctgtggcctaggctacctcaagactcacctcatccttaccgcacatttaaggcgccattgcttttgggagactggaaaagggaaggtgactgaaggctgtcaggattct 363217148_x_atcatctcctgcactggaaccagcagtgacgttgntggttataacnatgtctcctggtaccaacannacccaggcaaagcccccaaactcatgatttatgnngtcagtaatcggccctcaggggtttctaatcgcttctctg 364 217165_x_atgcgctggttcctgcaagtgcaaagagtgcaaatgcacctcctgcaagaagagctgctgctcctgctgccccgtgggctgtagcaagtgtgcccagggctgtgtttgcaaaggg 365 217179_x_ataggacagagggtcaccatctcttgctctggaagcagctccaacattgggaagaattatgtatcctggtaccagcaactcccaggaacagcccccaaactcctcatctataaaaataataagcgaccctcagggattcctgaccgattctctggctccaagtctggcacgtcagccaccctgggcatcaccagactccagactggggacgaggccgattattactgcggaacatgggatagcagcctgagtggtggccgggggatat 366217232_x_attgaggagaagtctgccgttactgccctgtggggcaaggtgaacgtggatgaagttggtggtgaggccctgggcaggctgctggtggtctacccttggacccagaggttctttgagtcctttggggatctgtccactcctgatgctgttatgggcaaccctaaggtgaaggctcatggcaagaaagtgctcggttctttgagtcctttggggatctgtccactcctgatgctgttatgggcaaccctaaggtgaaggctcatggcaagaaagtgctcggtgcctttagtgatggcctggctcacctggacaacctcaagggcacctttgccacactgagtgagctgcactgtgacaagctgcacgtggatcctgagaacttcaggctcctgggcaacgtgctggtctgtgtgctggcccatcactttggcaaaga 367 217235_x_atcagtgtccggatctcctggacagtcagtcaccatctcctgcaccggaaccagcagtgatgttggtggttataactatgtctcctggtaccaacagcacccaggcaaagcccccacactcatgatttatgatgtcattaagcggccctcaggggtccctgatcgcttctctggctccaaatctggcaacacggcctccctgaccatctctgggctccaggctgaggatgaggctgattattattgcagctcaaatgcaggcagtttttatgtct 368217258_x_attcctgcactgggagcagctcctacatcggggcaggttatgatgtacactggtaccggcaacttcccggcacagcccccaaactcctcatctatggtaacaccgatcggccctcaggggtccctgaccgattctctggctccaagtctggcatctcagcctccctggccatcactgggctccaggctgaggatgaggctgattattactgcaagtcctatgacagcagcctgag 369 217378_x_atgatgtgacatccaggtgacccagtctccatcttccctgtctgcgtctgtaggagacagagtcaccatcacctgccgggcaagtcagggcattagcaatgggttatcctggtatcagcagaaaccagggcaagcccctacgctcctgatctatgctgcatccagtttgcagtcgggggtcccatctcggttcagtggcagtggatctgggacagatttcactctcaccatcagcagcctgcagcctgaagatgttgc 370 217414_x_atggtccccacagactcagagagaacccaccatggtgctgtctcctgccgacaagaccaacgtcaaggccgcctggggtaaggtcggcgcgcacgctggcgagtatggtgcggaggccctggagaggcacttcgacctgagccacggctctgcccaagttaagggccacggcaagaaggtggccgacgcgctgaccaacgccgtggcgcacgtggacgacatgcccaacgcgctgtccgccctgagcgacctgcacgcgcacaagcttcgggtggacccggtcaacttcaagctaagccactgcctgctggtgaccctggccgcccacctccccgccgagttcacccctgcggtgcacgcttccctggacaagttcctggcttctgtgagcaccgtgctgacctccaaataccgttaagctggagcctcggtagcc 371 217480_x_atgctgccaggtgccagatgtgacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggcgagtcagggcattagcaataatttaaattggtatcagcagaaaccagggaaaactcctaagctcctgatctatgctgcacccagtctgcaaagtgggattccctctcggttcagtgacagtggatctggggcagattacactctcaccatccgcagcctgcagcctgaagattttgc 372 217546_atagtcgctccatttatcgcttgagatctccagccttaccgcggctcgaaatggaccccaactgctcctgcaccactggtgtctcctgcgcctgcaccggctcctgcaagtgcaaagagtgcaaatgcacctcctgcaagaagagctgctgctcctgctgccccgtgggctgtgccaagtgtgcccacggctgtgtctgcaaagggacgttggagaactgcagctgctgtgcctgatgtgggaacagctcttctcccagatgttaatagaacaagctgcacaacctggattttttttcaatacgatactgagccatttgct373 217757_atcctccagacctccttgaaatacaatattctcccagaaaaggaagagttcccctttgctttaggagtgcagactctgcctcaaacttgtgatgaacccaaagcccacaccagcttccaaatctccctaagtgtcagttacacagggagccgctctgcctccaacatggcgatcgttgatgtgaagatggtctctggcttcattcccctgaagccaacagtgaaaatgcttgaaagatctaaccatgtgagccggacagaagtcagcagcaaccatgtcttgatttaccttgataaggtgtcaaatcagacactgagcttgttcttcacggttctgcaagatgtcccagtaagagatctcaaaccagccatagtgaaagtctatgattactacgagacggatgagtttgcaatcgctgagtacaatgctccttgca 374 217762_s_atctattaccattctaactttcataaaaagttgggatcaagaagcagctgatttcctgccagggcttatattagggggntgattcttaaaggacattaggattggtgctcagaaatggttaatcatgctgtgtgctagccagggccagctggtaccttctttgccatgagcattcaagggacngctaacctttattgacaatctatatngcaaaagtcaggaaagaggttgtgagctgattggattaaagacctggcacttcagtaactcagcacgcttccacttcactcaacttaagagagttcattgacagtgttaggatgtgaaggctgggaaacacttattttgcttcaagagttccacttggctctcccaaataggtacctcaaaaactgttagcaagcggcatttggatgtcttgacaggggctttgcagggatttttagggttttttccacattgtccacattaatggttggcatgattgtgcttgcaggccaag 375217764_s_atgaatatgacgttaccttgcagactaaaaggttgaaggcccgaaactaacttttagctaacaataagggctgtgccccaatggaaactgagttcattttctgagaaaggtttggatgactgaaatatttcctctacagtcaaggactttggcatgcggtggctgaaactgagcttttttgtgtgggctccagttctcactgttctgcaatgctcatggcaagttgaatggtgagctagcttataaattaaagagctctgaactgtattcagaccgactgggtatctagcttactgttttaacatcattgttgaaaccagaccctgtagtccagtggtgctgccctgttgtgcaaactgctcctttttctcgtgtttttgtaaagagcttccatctgggctggacccagttcttgcacatacaagacaccgctgcagtcagctaggacctttccgccatgtattctattctgtagtaaagcatttccatcaacaatgcctaattgtatctgttatttttggtttaacacacactgattcatact376 217767_atggtctacgcctattacaacctggaggaaagctgtacccggttctaccatccggaaaaggaggatggaaagctgaacaagctctgccgtgatgaactgtgccgctgtgctgaggagaattgcttcatacaaaagtcggatgacaaggtcaccctggaagaacggctggacaaggcctgtgagccaggagtggactatgtgtacaagacccgactggtcaaggttcagctgtccaatgactttgacgagtacatcatggccattgagcagaccatcaagtcaggctcggatgaggtgcaggttggacagcagcgcacgttcatcagccccatcaagtgcagagaagccctgaagctggaggagaagaaacactacctcatgtggggtctctcctccgatttctggggagagaagcccaacctcagctacatcatcgggaaggacacttgggtggagcactggcctgaggaggacgaatgccaagacgaagagaaccagaaacaatgccaggacctcggcgccttcaccgagagcatggttgtc 377 217897_atcccctgcatatcttctcagcaataactccatgggctctgggacctacccttccaaccttccctgcttctgagacttcaatctacagcccagctcatccagatgcagactacagtccctgcaattgggtctctggcaggcaatagttgaaggactcctgttccgttggggccagcacaccgggatggatggagggagagcagaggcctttgcttctctgcctacgtccccttagatgggcagcagaggcaactcccgcatcctttgctctgcctgtcggtggtcagagcggtgagcgaggtgggttggagactcagcaggctccgtgcagcccttgggaacagtgagaggttgaaggtcataacgagagtgggaactcaacccagatcccgcccctcctgtcctctgtgttcccgcggaaaccaaccaaaccgtgcgctgtgacccattgctgttctctgtatcgtgatctatcctcaacaaca 378217967_s_atctcttttactactgacctttcacagagaaaaaatatttcccttgaaaaaaactgggcttgtcattttttcccttgtagctttaagcagagacataagtgccttgcattacacatagtaaactttctttaaaaaaaaaaaaaaaagattttggagactaccagggtaagattccaacttgtccaaaagctttctggccttacatattttattataaaaattctcaagtctggtaatcttctatgtcagagctagtgatttcaaaaggtttcacaattccccaagacaaaagtgattttcgttcattataataaggttaagtgatatgtgattcataacaattttgatgtgaagaagggaaggacatcattgacttaataatagtatcagtcggtgcaacagttggcaacatgtgccttcacactttaccataaagagacgggtttgagggtttgccttctaaagtctgcaacttcaagaaaaaaaatcgacactgtggattgactttcccggt379 218087_s_ataactttgtatagcccatgtacctaccttgtatagaaaaataattttaaaaatttgaatggaagggggtaaaggaagtcatgaagtttttttgcatttttatttaaatgaaggaattccaaataactcacctacagatttttagcacaaaaatagccattgtaaagtgttaaaatttacgataagtattctattggggaggaaaggtaactctgatctcagttacagtttttttttcctttttaatttcattattttgggtttttggtttttgcagtcctatttatctgcagtcgtattaagtcctattgctagaataggttactacaaaaaaggttatattctgaaagaaaaataactgacattatatataaccaattaatttaaagtattgccatttaaattacacactgagagcatgtcctatgcagacatagatttttctgttcatttatttttcttcattgcagtggattgatttgataaatagatgtgttgaattactacatttgctgtacatat 380218162_atggagctagccttgttttttgcatctttctcactcccatacatttatattatatccccactaaatttcttgttcctcattcttcaaatttgggccagttgtggctcaaatcctctatatttttagccaatggcaatcaaattctttcagctcctttgtttcatacggaactccagatcctgagtaatccttttagagcccgaagagtcaaaaccctcaatgttccctcctgctctcctgccccatgtcaacaaatttcaggctaaggatgccccagacccagggctctaaccttgtatgcgggcaggcccagggagcaggcagcagtgttcttcccctcagagtgacttggggagggagaaataggaggagacgtccagctctgtcctctcttcctcactcctcccttcagtgtcctgaggaacaggactttctccacattgttttgta 381 218224_atgcgggtcttgctggctaaaatgcccaggtaaagggttggttggacacagcgcttagtgcacgctgtcatcatggacatcataatcagttgtgaaaaacacgcgaacctatgacacttcttattccacactgaatgtgaaattgcatgttcagatgtttnactacgaggcctggctcacaggaagtgttcagtaaaagtatgcactgttagattactgataacgcggatagatttttgttnaccataaattgttccagatttatattaatggaaggaagtgtgcatttattagctattantcaactttacaangcaaacatcttatttctcatctttaaacatgtcgaccagtttaattgaaaagtattctgagactgcaaaatggggtgttaaaaaatactgcagttacggagctgtgtaaaccagtttctcattgcataagatacagatgtaaattgcatggagaggttgatatgcacctgtacagtaattcactcccccatttcacttctttgtcagagaatagttcttgttcatactgagtgtt382 218312_s_atgcatccgaggggagccgccggatgtggaagaagactcggctttcctgcagccatttagtgccgccccatgctaggttatttgacattgtgcagtgtagagttgccttaaagtgcgtgatctgccagtgctttcttcaagtcacccttgccccgattcctcatgtttgcgctccccagggttgctcaagtggaaattttgtcagctgtttagccttttcgtacttggcgtgatgtcaacttcacttctaatctgcaaaagcagaagctgtttcctagtttacctcgcgtgtgtttacctatatggagtagctcgcagagatcacagaaatgcttgcagcctaaggcagggttttcagaccgtgggtcccagcccatttagtaaaatgggaaatcaattagcaagtggtcaccagcattacacagca383 218353_attatacagtttaataagcctcttgcaagttacttgttctctcacctgaggtatttttttcctccccaccttgcccctgttcctcccttcctcttctccctttgcaagaggaaatatttaacatatttgggtccaacttcaataatgtaataattaatacattaaaagcatttaacttcctttctagaaaaatgcacaggctaaggcatagacaaaacaaagagaaatgctgagaaatttgccactggagacaagcaatctgaataaatatttgccaaaagttctttttatgtcatatagtgtcaggatttgaaggagctattttttttaatgttgcaactagcaactcatcttcggaagacacagccaggagaatgaagtagaagtgaaaggtttataaatccatttgtaagcatttatcccatatattttaaattcaagaaaaattgtgtttatctttagaattttgtattcaatactttatgtactatgtgactcatgcttctggataaataaagcaccaaatatgtatctgtaaccacaatcacacata384 218418_s_atggcttgatgtagactggcttgctttgatttttagtgaagggaatgtacgtaaaacaaaatagggcttggctggtcaaaggagacaagcaggatggatggatggatggatgaatagatagatggtgtttgcatgtaaattgcagagaaaacaaaaccaaagctgattggaaacaattaattgtgggtgtctgagggggaaggtcgcagctttgggcagctttgagaagcggtacaagagctctgtgcctgtgtgtccagccctggagccagccagtgcatttattttaagctcttagaagcaactccttggcccaggaatgcgtgacccctgagatgggtccacgcatctctctacacgtccttctctccgtgggatactggactcgtgcctctgcgcccattctcttctcacgcatatccatgagctttaatttcactttctgatcacggtacgtccataaagccagt 385 218468_s_atggagatgacttaagttggcagcagtaatcttcttttaggagcttgtaccacagtcttgcacataagtgcagatttgccccaagtaaagagaatttcctcaacactaacttcacggggataatcaccacgtaactacccttaaagcatatcactagccaaagaggggaatatctgttcttcttactgtgcctatattaagactagtacaaatgtggtgtgtcttccaactttcattgaaaatgccatatctataccatattttattcgagtcactgatgatgtaatgatatattttttcattattatagtagaatatttttatggcaagagatttgtggtcttgatcatacctatt 386 218469_atgaagctgacacaccgtatgttgttagagtcttttatctggtcaggggaaacaaaatcttgacccagctgaacatgtcttcctgagtcagtgcctgaatctttattttttaaattgaatgttccttaaaggttaacatttctaaagcaatattaagaaagactttaaatgttattttggaagacttacgatgcatgtatacaaacgaatagcagataatgatgactagttcacacataaagtccttttaaggagaaaatctaaaatgaaaagtggataaacagaacatttataagtgatcagttaatgcctaagagtgaaagtagttctattgacattcctcaagatatttaatatcaactgcattatgtattatgtctgcttaaatcatttaaaaacggcaaagaattatatagactatgaggtaccttgctgtgtaggaggatgaaaggggagttgatagtctcataaaactaatttggcttcaagtttcatgaatctgtaactagaatttaattttcaccccaataatgttctatatagcctttgctaa387 218541_s_atgttcaaaatatttccaagcctgagtattgtctattggtatagatttttagaaatcaataattgattatttatttgcacttattacaatgcctgaaaaagtgcaccacatggatgttaagtagaaattcaagaaagtaagatgtcttcagcaactcagtaaaaccttacgccaccttttggtttgtaagaggttttttatacatttcaaacaggttgcacaaaagttaaaataatggggtcttttataaatccaaagtactgtgaaaacattttacatattttttaaatcttctgactaatgctaaaacgtaatctaattaaatttcatacagttactgcagtaagcattaggaagtgaatatgatatacaaaatagtttataaagactctatagtttctataatttattttactggcaaatgtcatgcaacaa388 218546_atggcagcccacaagtttctcgtggggagatggaggcagagcccagggtaggggacagagctgctggggcctttccttgcctgggaatctgtcccaggaagagcttccccactcccatcccccaaattggaaaaaccgtacattcaagcctgtttggccctgaaattcttaagaatctggttaagaattaactcactaatgtcaaaagtcaaaacctcctaggggttgtcctgggagtcaggttcacgggtacagaagatgaatctcagatgtcactcaacctgagccgtcattctctgtggcagggctgccctgggtttctcttactcaatccctggagtgtaagcatttggattgtgtcacagattacctttttaccttttctttctttttttttctttttttcaatatcagtgcccacaccttactgagtattgagttttagagctttcgcttgatgtgcttgaccaagagacttcttttgtatccttttct 389 218559_s_attcaagtgcgttctttagaccaatgcattgcgtttctttccctgcttttgagatagtaggaagagttcttggtggtgtccccccccttcaattcttcagttgtatagtagttatagggaagatatgggtgtttttctttattattacttttttttttctgcaggtcagtaaaaggatttaagttgcactgacaaaaataccaaaataaaagtgtatttttaagttcccatttgaaattgctggcgctgctggccggatgcatttttgagtttgtattagttgataaattaacagtaataacaagattgtatgaaccgcatggtgcttgcagttttaaatattgtggatatttgtcctgcatcagaaacgagctttggtttttacagattcaactgtgttgaaatcaaacctgccgcaacagaaattgtttttatttcatgtaaaataagggatcaatttcaaaccctgcttatg 390 218756_s_atcctcctgcctctggattttaggtgttgatttctggatcacgggataccacttcctgtccacaccccgaccaggggctagaaaatttgtttgagatttttatatcatcttgtcaaattgcttcagttgtaaatgtgaaaaatgggctggggaaaggaggtggtgtccctaattgttttacttgttaacttgttcttgtgcccctgggcacttggcctttgtctgctctcagtgtcttccctttgacatgggaaaggagttgtggccaaaatccccatcttcttgcacctcaacgtctgtggctcagggctggggtggcagagggaggccttcaccttatatctgtgttgttatccagggctccagacttcctcctctgcctgccccactgcaccctctcccccttatctatctccttctcggctccccagcccagtcttggcttcttgtcccctcctggggtcatccctccactctgactctgactatggcagcag 391 219014_atggcatgtgtgactgtttcagcgactgcggagtctgtctctgtggcacattttgtttcccgtgccttgggtgtcaagttgcagctgatatgaatgaatgctgtctgtgtggaacaagcgtcgcaatgaggactctctacaggacccgatatggcatccctggatctatttgtgatgactatatggcaactctttgctgtcctcattgtactctttgccaaatcaagagagatatcaacagaaggagagccatgcgtactttctaaaaactgatggtgaaaagctcttaccgaagcaacaaaattcagcagacacctcttcagcttgagttcttcaccatcttttgcaactgaaatatgatggatatgcttaagtacaactgatggcatgaaaaaaatcaaatttttgatttattataaatgaatgttgtccctgaacttagctaaatggtgcaacttagtttctccttgctttcatattatcg 392 219059_s_atagagaatgcccttctccttattgtaaccctgtctggatcctatcctcctacctccaaagcttcccacggcctttctagcctggctatgtcctaataatatcccactgggagaaaggagttttgncaaagtgcaaggacctaaaacatctcatcagtatccagtggtaaaaaggcctcctggctgtctgaggctaggtgggttgaaagccaaggagtcactgagaccaaggctttctctactgattccgcagctcagaccctttcttcagctctgaaagagaaacacgtatcccacctgacatgtccttctgagcccggtaagagcaaaagaatggcagaaaagtttagcccctgaaagccatggagattctcataacttgagacctaatctctgtaaagctaaaataaagaaatagaacaaggctgaggatacgacagtacactgtcagcagggactgtaaacacagacagggtcaaagtgttttctctgaacacattgagttggaatcactgtttagaacacacacacttactttttctggtctctaccactgctgatattttct 393 219087_atattaccttatcatgtcttagagcccgtctttatgtttaaaactaatttcttaaaataaagccttcagtaaatgttcattaccaacttgataaatgctactcataagagctggtttggggctatagcatatgcttttttttttttaattattacctgatttaaaaatctctgtaaaaacgtgtagtgtttcataaaatctgtaactcgcattttaatgatccgctattataagcttttaatagcatgaaaattgttaggctatataacattgccacttcaactctaaggaatatttttgagatatccctttggaagaccttgcttggaagagcctggacactaacaattctacaccaaattgtctcttcaaatacgtatggactggataactctgagaaacacatctagtataactgaataagcagagcatcaaattaaacagacagaaaccgaaagctctatataaatgctcagagttctttatgtatt 394 219508_atatggggctggggacttgaattggatgcttcaaaaccatcacctgttggccaacaagtttgacccaaaggtagatgataatgctcttcagtgcttagaagaatacctacgttataaggccatctatgggactgaactttgagacacactatgagagcgttgctacctgtggggcaagagcatgtacaaacatgctcagaacttgctgggacagtgtgggtgggagaccagggctttgcaattcgtggcatcctttaggataagagggctgctattagattgtgggtaagtagatcttttgccttgcaaattgctgcctgggtgaatgctgcttgttctctcacccctaaccctagtagttcctccactaactttctcactaagtgagaatgagaactgctgtgatagggagagtgaaggagggatatgtggtagagcacttgatttcagttgaatgcctgctggtagcttttccattctgtggagctgccgttcctaataattccag395 219543_atggaattcttctcttacttcaataaaatgggttttaacataactttaaattcagttaaatatacaatattgaatacctatagttgactttgggatggggactttttcaagtcattaagagtgtttgtttaaggtgatctcattgatggtagttctcagccgtctcaaaaactgcaagctaatcagtcagacattctttaatgaccccaattttttcactttaattgttaccatgttttctatttttactgatttttgctaaagcatgtaagagtgaatttattatagcagtaatcttgtgtttctcctgatgtgca396 219607_s_atatcaacacatttagcttggcgttttattcattccatcacccttactgtaactactatggcaactcaaataattgtcatgggactatgtccatcttaatgggtctggatggcatggtgctcctcttaagtgtgctggaattctgcattgctgtgtccctctctgcctttggatgtaaagtgctctgttgtacccctggtggggttgtgttaattctgccatcacattctcacatggcagaaacagcatctcccacaccacttaatgaggtttgaggccacccaaagatcaacagacaaatgctccagaaatctatgctgactgtgacacaag397 219669_atcatctctcaggaggtgggctgtccaccaaaatgagcattcagggctgcgtggcccaaccttccagcttcttgttgaaccacaccagacaaatcgggatcttctctgcgcgtgagaagcgtgatgtgcagcctcctgcctctcagcatgagggaggtggggctgagggcctggagtctctcacttggggggtggggctggcactggccccagcgctgtggtggggagtggtttgcccttcctgctaactctattacccccacgattcttcaccgctgctgaccacccacactcaacctccctctgacctcataacctaatggccttggacaccagattctttcccattctgtccatgaatcatcttccccacacacaatcattcatatctactcacctaacagcaacactggggagagcctggagcatccggacttgccctatgggagag 398 219796_s_attccttgtccacaagcactatggcccccggctcaagtgctgctctggcaaagctccggagccccagccccaaggctttgacaaccaggcgttcctccctgaccacaaggccaactgggcgcccgtccccagccccacgcacgaccccaagcccgcggaggcaccgatgcccgcagagcccgcaccccccggccctgcctccccaggcggtgcccctgagccccccgcagcggcccgagctggcggaagccccacggcggtgaggtccatcctgaccaaggagcggcggccagagggcgggtacaaggctgtctggtttggcgaggacatcgggacggaggcagacgtggtcgttctcaacgcgcccaccctggacgtggatggcgccagtgactccggcagcggcgatgagggcgagggcgcggggaggggtgggggtccctacgatgcgcccggtggtgatgactcctacatctaagtggccc399 219799_s_ataccatcgctggtggtatcccagggtccctgctcaagttttctttgaaaaggagggctggaatggtacatcacataggcaagtcctgccctgtatttaggctttgcctgcttggtgtgatgtaagggaaattgaaagacttgcccattcaaaatgatctttaccgtggcctgccccatgcttatggtccccagcatttacagtaacttgtgaatgttaagtatcatctcttatctaaatatt 400 219948_x_atgaatactcataattcttatctctataatcaaaagtataatttactgtagaaaaataaagagatgcttgttctgaaagtaagatcagtgaactgcttttcagtctcaatctttgagaattgtaaattcatcaaataattgcttacatagtaaaaatttaaggtattagaaaacctgcataacaaatagtattatatattaaatattttgatatgtaaagctctacacaaagctaaatatagtgtaataatgtttacactaataagcaaatatgttaatcttctcatttttttactgtcatataatcttagtgatatgcctattaatagttttaaataaataaattggctcatctggctttttgaaaattttgaaattcttacagatgttgattaggtatatctacaaattaatttcaattttaaaatgatgatataaaaataaatataagtatttttcttgtgtatgtata 401 220026_atagtaactttgtttatccctcaagcaaatcctgatgacattgatcctactcctactcctactcctactcctgataaaagtcataattctggagttaatatttctacgctggtattgtctgtgattgggtctgttgtaattgttaactttattttaagtaccaccatttgaaccttaacgaagaaaaaaatcttcaagtagacctagaagagagttttaaaaaacaaaacaatgtaagtaaaggatatttctgaatcttaaaattcatcccatgtgtgatcataaactcataaaaataattttaagatgtcggaaaaggatactttgattaaataaaaacactcatggatatgtaaaaactgtcaagattaaaatttaatagtttcatttatttgttattttatttgtaagaaatagtgatgaacaaagatcctttttcatactgatacctggttgtatattatttgatgcaacagttttctgaaatgat 402 220037_s_atttccacttctattccacggagaaaaaaattgatttgtgtcacagaagtttttatggaaactagcaccatgtctacagaaactgaaccatttgttgaaaataaagcagcattcaagaatgaagctgctgggtttggaggtgtccccacggctctgctagtgcttgctctcctcttctttggtgctgcagctggtcttggattttgctatgtcaaaaggtatgtgaaggccttcccttttacaaacaagaatcagcagaaggaaatgatcgaaaccaaagtagtaaaggaggagaaggccaatgatagcaaccctaatgaggaatcaaagaaaactgataaaaacccagaagagtccaagagtccaagcaaaactaccgtgcgatgcctggaagctgaagtttagatga403 220075_s_atctcaactcggccatcacatatcgaattaccaaccactcacacttccggatggagggagaggttgtgctgaccaccaccacactggcacaggcgggagccttctacgcagaggttgaggcc 404 220266_s_attccattaccaagagctcatgccacccggttcctgcatgccagaggagcccaagccaaagaggggaagacgatcgtggccccggaaaaggaccgccacccacacttgtgattacgcgggctgcggcaaaacctacacaaagagttcccatctcaaggcacacctgcgaacccacacaggtgagaaaccttaccactgtgactgggacggctgtggatggaaattcgcccgctcagatgaactgaccaggcactaccgtaaacacacggggcaccgcccgttccagtgccaaaaatgcgaccgagcattttccaggtcggacc 405 220376_ataaaacccattctttcagttacatctactaagagctcgtagttcaataacattccaaagaacgtagtttggaaaacactggcctatcggctgtaataggaagggtctaaagaaaattatttgctgagtcctcataatcaattggctataatcacaatttaataatttatcaatgcaaacagtacattaaaaactgtagcacaatctataatttttaccttcatatgcagagaaattaagaatttacatcttttacaaatatgtgtatctctgaaataatgaaatatattgatgggtgaaataatatttctggtattttcttcattataacacgtggaatgggacagtggctagaggtatggatggagcaaggtcaaatatgagctgatggagctgggcgctaaataagggtataatatgctacttctgtgtatgttgtgtatggtatagtatgctatttctgtgtatgttcaaattgtttatgtatataataaagttttaaaaatttgtatgtacttgacaattccttagaa406 220468_atagaggagacactttggcgttcttcaagcagaactgaggctgcgaaaaatccaagtctctacagagacactgatgaagttgaaagggtaattgtttttccatgccaaatgaggaaatcaaattaatgagttgacaaacttttcctgagatgttatttcatctacatttagttaaacaacttagaatgatatctagaaaatatttattttcagccaggaactttagcaaactgtggcaatgatcactgggaatgaaaacgtataatgttctacaatttttgttatcacattggatgactttgaatatagtagtgacacttgggaccaaataaattattttatatgactactagaacaaagttttagtaagctgtctgctaatagagtcagaattcttccagattgtttccagctgtaacaggtattgaatttccaccgtgctcctatgtaacagctgggtggtgtaaaaaatgaacttcaaattatggagtggaagaagcgtaatgttaatatcttgtaaattcgtattccctat407 220645_atcattttccaggatctcagtgtgagtatcattgatgcctgggatataacaattgcatatggcacaaataatgtacacccacctcaacatgtagtcggaaatcagattaatatattattaaactatatttgttaaataacacaaaagtctgaaattcattcacttaagtaaaaaaatttattgactgtctactagcaggccagatgctgtgtttggctctgaattcccaactagcaagagcagagaatctacattatggctgatccataagccaccaattcagctaaatgagatgtttctaatctgggcttccacttaaaaataaaactaaaaatactcatgaaaagagcctacccttcttgatcagagccatacccctcttcaccaatgggaagt 408220812_s_atggtattttagtctagttttatatgaacggttgtatcagggtaaccaactcgatttgggatgaatcttagggcaccaaagactaagacagtatctttaagattgctagggaaaagggccctatgtgtcaggcctctgagcccaagccaagcatcgcatcccctgtgatttgcacgtatacatccagatggcctaaagtaactgaagatccacaaaagaagtaaaaatagccttaactgatgacattccaccattgtgatttgttcctgccccaccctaactgatcaatgtactttgtaatctcccccacccttaagaaggtactttgtaatcttccccacccttaagaaggttctttgtaattctccccacccttgagaatgtactttgtgagatccaccctgcccacaaaacattgctcttaacttcaccgcctaacccaaaacctataagaactaatgataatccatcacccttcgc 409 220834_atgctggccaagactactgggccgtgctttctggaaaaggcatttcagccacgctgatgatcttctccctcttggagttcttcgtagcttgtgccacagcccattttgccaaccaagcaaacaccacaaccaatatgtctgtcctggttattccaaatatgtatgaaagcaaccctgtgacaccagcgtcttcttcagctcctcccagatgcaacaactactcagctaatgcccctaaatagtaaaagaaaaaggggtatcagtctaatctcatggagaaaaactacttgcaaaaacttcttaagaagatgtcttttattgtctacaatgatttctagtctttaaaaactgtgtttgagatttgtttttaggttggtcgctaatgatggctgtatctcccttcactgtctcttcctacattaccactactacatgctggcaaaggtgaaggatcagaggactgaaaaatgattctgcaactctcttaaa 410 221004_s_atagcccaccagcaggagcttggagtttggggagtggggatgagtccgtcaagcacaactgttctctgagtggaaccaaagaagcaaggagctaggacccccagtcctgccccccaggagcacaagcagggtcccctcagtcaaggcagtgggatgggcggctgaggaacggggcaggcaaggtcactgctcagtcacgtccacgggggacgagccgtgggttctgctgagtaggtggagctcattgctttctccaagcttggaactgttttgaaagataacacagagggaaagggagagccacctggtacttgt 411 221305_s_atgccactatcttgaagaaggtgcacagtgccctgctcctctttcctatgtccccagaattctcttagggttctcagatgccatgactttcaaggagagagtacggaaccacatcatgcacttggaggaacatttattttgccagtatttttccaaaaatgccctagaaatagcctctgaaattctccaaacacctgtcacagcatatgatctctacagccacacatcaatttggttgttgcgaacagactttgttttggactatcccaaacccgtgatgcccaatatgatcttcattggtggtatcaactgccatcagggaaagcc412 221541_atctttatcatccccacaaacattttgaaactggaatatttgtcttcagaaaatggaaacaagactataaatgataagccctgtccctagcaccacctctcctgtgtgtggaatagaggcccctcgtgctaccaacacttaccctgtgtttaaaaagatcttgtaccaagccaacggcgttcctggctctcctgcccacaggatgaacattttcggcttccttaggagttttgccctaccgtattccaaagcgtgtgctggtttctcatattgtctgtaggctcac 413221584_s_atgtgaggctcagtcagaacctccaccctcccccacaccaaagacaggggcagcgtagtattcaaaccagtattgtggtggggaataattgtatacatgtaaattatcaagccctatgagtggaagaattttttcaaattatttttgtctctctatatattgatttatattatgtataactatctctttatataaactatatataattatatatatataactatataattatatatatataactatatatataactatatatatgtatcccctagtattggatcatgaagagctcttcatgcattctttgcaaaggaggttataaagttacgccctcagaacatttataactataagaatgtgccagttaaagtgctcaacaggaaatatgacagtttaaaagcattgtaaaactcacatagcttacttctctctctaaagtgcaacaaggatgaatagaatgggccaaggtatgacaattaatggttctgcatgacctagccactgctgggggttttcttctataacgttgtccttgtga414 221667_s_atgggacttaacatttcacgttgtatcttacttgcagtgaatgcaagggttacttttctctggggacctcccccatcacccaggttcctactctgggctcccgattcccatggctcccaaaccatgccgcatggtttggttaatgaaacccagtagctaaccccactgtgcttccacatgcctggcctaaaatgggtgatatacaggtcttatatccccatatggaatttatccatcaaccacataaaaacaaacagtgccttctgccctctgcccagatgtgtccagcacgttctcaaagtttccacattagcactccctaaggacgctgggagcctgtcagtttatgatctgacctaggtcccccctttcttctgtcccctgtttttaagtccggatttttacagaaggaactgtctccagacagctcatcaaggaaccaagcaaaggccagatagcctgacagataggctagtggtaattgtgtatatgggcgggacgtgtgtgtcatta415 221747_atcctctgtcctcaaatgtccaaaatgttggaggacctctgttcatatcccacgcctgggctcttgccagcagtggagttactgtagagggatgtcccaagcttgttttaccaatcagtgttaagctgtttgaaactctcctgtgtctgtgttttgtttgtgcgtgtgtgtgagagcacatcagtgtgtgcaggctgtgtttccccatttctctcctcccttcagacccatcattgagaacaaatgtaagaaatcccttcccaccaccctccctgcctcccaggccctctgcgggggaaacaagatcacccagcatcct416 221748_s_atatattttgtatcatcgtgcctatagccgctgccaccgtgtataaatcctggtgtntgctccttatcctggacatgaatgtattgtacactgacgcgtccccactcctgtacagctgctttgtttctttgcaatgcattgtatggcttta 417 221841_s_atatccgacttgaatattcctggacttacanaatgccaagggggtgactggaagttgtggatatcagggtataaattatatccgtgagttgggggagggaagaccagaattcccttgaattgtgtattgatgcaatataagcataaaagatcaccttgtattctctttaccttctaaaagccattattatgatgttagaagaagaggaagaaattcaggtacagaaaacatgtttaaatagcctaaatgatggtgcttggtgagtcttggttctaaaggtaccaaacaaggaagccaaagttttcaaactgctgcatactttgacaaggaaaatctatatttgtcttccgatcaacatttatgacctaagtcaggtaatatacctggtttacttctttagcatttttatgcagacagtctgttatgcactgtggtttcagatgtgcaataatttgtacaatggtttattcccaagtatgccttaagcagaacaaatgtgtttttctatatagttccttgccttaa418 221896_s_atccaatcctgaaggtactccctgtttgctgcagaatgtcagatattttggatgttgcataagagtcctatttgccccagttaattcaacttttgtctgcctgttttgtggactggctggctctgttagaactctgtccaaaaagtgcatggaatataacttgtaaagcttcccacaattgacaatatatatgcatgtgtttaaaccaaatccagaaagcttaaacaatagagctgcataatagtatttattaaagaatcacaactgtaaacatgagaataacttaaggattctagtttagttttttgtaattgcaaattatatttttgctgctgatatattagaataatttttaaatgtcatcttgaaatagaaatatgtattttaagcactcacgcaaaggtaaatgaacacgttttaaatgtgtgtgttgctaattttttccataagaattgtaaacattgaactgaacaaattacctataatggatttggttaatgacttatgagcaagctggtttggccagacagtatacccaaacttttatataatatacagaaggctatcacacttgtgaa 419 222043_attcgactctgctgctcatgggaagaacagaattgctcctgcatgcaactaattcaataaaactgtcttgtgagctgatcgcttggagggtcctctttttatgttgagttgctgcttcccggcatgccttcattttgctatggggggcaggcaggggggatggaaaataagtagaaacaaaaaagcagtggctaagatggtatagggactgtcataccagtgaagaataaaagggtgaagaataaaagggatatgatgacaaggttgatccacttcaagaattgcttgctttcaggaagagagatgtgtttcaacaagccaacta 420 222162_s_ataataacgcaaatggcttcctctttcctttttttggaccatctcagtctttatttgtgtaattcattttgaggaaaaaacaactccatgtatttattcaagtgcattaaagtctacaatggaaaaaaagcagtgaagcattagatgctggtaaaagctagaggagacacaatgagcttagtacctccaatttcctttctttcctaccatgtaaccctgctttgggaatatggatgtaaagaagtaacttgtgtctcatgaaaatcagtacaatcacacaaggaggatgaaacgccggaacaaaaatgaggtgtgtagaacagggtcccacaggtttggggacattgagatcacttgtcttgtggtggggaggctgctgaggggtagcaggtccatctccagcagctggtccaacagtcgtatcctggtgaatgtctgttcagctcttct 421 222453_attcaaatggaacctgccctctaaagcactttctttcctttacttgcgtggtttcatgtaagctgtgctgtttagaaacaacatctcagactttacaaagaaatgacaaagaaggcaattgcactttttaagggatatcgacaagcagtttctgttttctaaaggacaaaatacagagtgtgtgtcatttttaattagattctttcccctgctgagttggaaattccagtgcagcactgattgaccacagttgccaatctaaaagcacaaagacagaagtaaagctttatgctaattttatttcaatatgatagaaaatttatcttggtatgtccttttttagataactccagcaggaaactgtaactgctatgtctttaggaaaacgtagaagaaagaacattattattctttaattcctacaaggtacttgaaaaccttaagtgaaaaagatttctatctttttatcttggcgcatt 422 222513_s_attgccactaattcattcacactaaggtgtaaatgattgataataggaatgagttacctcttcccacagacatttgtttttaagtatgacagagcagggccttaatcccaagggaaaaggttatggaactggagggggtgagctttctgggtagaaggagacttcctgaatttccttaaaacccagtaagagtaagacctgttgttttggaaggtctgctccaccatctaagagcactgtttttttttttttgttgttgttgttgttttacggtctctgagggaatatagtaaaaatgcatatgcacgtgcaatttgcacggcagcatttcaccgattgtggactgtattggctaatgtgtttcctggtctttagatgcaaaccattaataacactatcttatctcatagttttttcaggggtgcttcttgattagtagggaattttgaacacctctttaaatacagctagaaaataaaaccaatttgtaaagccacatttgcatatgatgccagcctcacgcatttgtatatctccagaaattcaggtatgcctcaccaatttgcccgtctttaataa 423 222717_attaaactaacccttacattccatgtgatgtgatgtaggcttataagntgctaaaatctataggtntnggaagtgaaagattctattttttcttttttngtacataatgggaatttcattccagattatattttatttacatattaatttcacagaatattaatatttcttaacttcttaaagcatgctagcgttttatgtatatgtacacatatattcagacagggtaattttatctgctgcctaacattgtactaaaatattgctttatctgtttttaattacaaaatgctaatgatttcttaaattatagtttaaagacaattggcccaggaagcaaatcccctgcctttagtatgaaccactataagtaaccttacaaatagagttaatccaagacaatattaacaaactgtgctttgtctttaataaaagggataggattaacaaacatattgatggcataacctattcagctatgtccttatttttgcaataatgtaacctcaaatattggattgttgaaccaacaatggctgtgttaaa424 222722_attttatgatgactcagtggtgccagagtaaagtttctaaaataacattcctctcacttgtaccccactaaaagtattagnctacacattacattgaagttaaacacaaaattatcagtgttttagaaacatgagtccggactgtgtaagtaaaagtacaaacattatttccaccataaagtatgtattgaaatcaagttgtctctgtgtacagaatacatacttattcccatttttaagcatttgcttctgttttccctacctagaatgtcagatgtttttcagttatctccccatttgtcaaagttgacctcaagataacatttttcattaaagcatctgagatctaagaacacaattattattctaacaatgattattagctcattcacttattttgataactaatgatcacagctattatactactttctcgttattttgtgtgcatgcctcatttccctgacttaaacctcactgagagcgcaaaatgcagctttatactttttacttt 425223121_s_atgataacctacatcaaccgagataccaaaatcatcctggagaccaagagcaagaccatttacaagctgaacggtgtgtccgaaagggacctgaagaaatcggtgctgtggctcaaagacagcttgcagtgcacctgtgaggagatgaacgacatcaacgcgccctatctggtcatgggacagaaacagggtggggagctggtgatcacctcggtgaagcggtggcagaaggggcagagagagttcaagcgcatctcccgcagcatccgcaagctgcagtgctagtcccggcatcctgatggctccgacaggcctgctccagagcacggctgaccatttctgctccgggatctcagctcccgttccccaagcacactcctagctgctccagtctcagcctgggcagcttccccctgccttttgcacgtttgcatccccagcatttcctgagttataaggccacaggagtggatagctgttttcacctaaaggaaaagcccacccgaatcttgtagaaat426 223122_s_atggtgcaactgtgacttgggtctggttggttgttgtttgttgttttgagtcagctgattttcacttcccactgaggttgtcataacatgcaaattgcttcaattttctctgtggcccaaacttgtgggtcacaaaccctgttgagataaagctggctgttatctcaacatcttcatcagctccagactgagactcagtgtctaagtcttacaacaattcatcattttataccttcaatgggaacttaaactgttacatgtatcacattccagctacaatacttccatttattagaagcacattaaccatttctatagcatgatttcttcaagtaaaaggcaaaagatataaattttataattgacttgagtactttaagccttgtttaaaacatttcttacttaacttttgcaaattaaacccattgtagcttacctgtaat427 223235_s_atagggtacgagaacttgccaatgggaaattcatccgagtggcactggcagagaaggataggagtggaatgcccacacagtgaccaacagaactggtctgcgtgcataaccagctgccaccctcaggcctgggccccagagctcagggcacccagtgtcttaaggaaccatttggaggacagtctgagagcaggaacttcaagctgtgattctatctcggctcagacttttggttggaaaaagatcttcatggccccaaatcccctgagacatgccttgtagaatgattttgtgatgttgtgatgcttgtggagcatcgcgtaaggcttcttgcttatttaaactgtgcaaggtaaaaatcaagcctttggagccacag 428223343_atgagtccaaatgtcatcagtgctcattttgagataccctgctatcgatggtcgctacaaaccaggaaatactcaagttattatgtgtatacattggntttagntttatgaaacaatttaccttcatgatctcatagttaaaattgtaataaatttaggaatataaaggatcaatatgggaagcaaaatttctaaaggcagtttctgttgttttaattagtatttgtgtagttcaaaccaggaaggatttgactatcattagattttgcttaactttatgaaagctaaaatattctctgttataaaggggcaactccatctggtcctatagcatctttactactgatttttttttngtttaatttgaaaatgcaaagaattgttaaatgttcttaaatgttctcactacaaaaaaagaaaaaagataactacgtgaggtgatggatatgttaattagctggattgtggtaatcattttggaatgtatatgtatatcaaaacatgtagtacaccctaaatatat429 223395_atagatacatttttacccaccataaatgttacaatatctgaatatgctttgtcaaactatccctttatgcaatcgtcttcatattgtttttatgattctaatcaagctgtatgtagagactgaatgtgaagtcaagtctgagcacaaaaagataatgcacgatgagattgcctaccattttataggatatttactatgtatttatacgttaagacctctatgaatgaatgtatcagagaatgtctttgtaactgtttaattcaatctgtaataaaaatctaactaactaactcatttatttctattaaaaaggtattgtcctttaggcggggaatgggaatccttgctgcactgttgcagtcattctgaaaggacctttccctgtacttacctttcaacatgcttcaatcttatcaacgctacat430 223484_atgaaaaccgatgtgatccttgatcgaaaaaaaaatccagaaccttgggaaactgtggaccctactgtacctcaaaagcttataacaatcaaccaacaatggaaacccattgaagagttgcaaaatgtccaaagggtgaccaaatgacgagccctcgcctctttcttctgaagagtactctataaatctagtggaaacatttctgcacaaactagattctggacaccagtgtgcggaaatgcttctgctacatttttagggtttgtctacattttttgggctctggataaggaattaaaggagtgcagcaataactgcactgtctaaaagtttgtgcttattttcttgtaaatttgaatattgcatattgaaatttttgtttgatctatgaatgtttttcttaaaatttacaaagctttgtaaattagattttctttaataaaatgccatttgtgcaagatttct 431 223551_ataattgtgttgtgatgctactcactttgattgcaatgatgatgtccaaggtaagctattaaaaggcaggttacttccaaatcgcactgaaggaaaaggttaagaataatacatgatcacagaaatgcataccactgtctgtaaacccaacaaaattcactgttctcttttggatttatttagcctgatgtatttttaattcaatttttatggtgatgggcaaatcattcttggtaaatgtaaatcaaacatgattgatttaaaacttcatggaatttgtagaaaattatggacatttttggtgagaaagaacaatagtcaaaactcacatggatagagtgtgtttgttttttgccaaaaatgccccagaccttttcccaaacctcaaaaacgtcttggaaaaattgtaaaagtttgataacagaaacatctttaggatatttttgtctgacgtattttgcttctagtatgtgcctactgtgatttttttcatgtggaaaatgcaaaatttgtaacaaaatggttatatggaacatgcctattaaacgaa432 223597_atggcatctggcacgtgcccaataagtcccccatgcagcactggagaaacagctccctgctgaggtaccgcacggacactggcttcctccagacactgggacataatctgtttggcatctaccagaaatatccagtgaaatatggagaaggaaagtgttggactgacaacggcccggtgatccctgtggtctatgattttggcgacgcccagaaaacagcatcttattactcaccctatggccagcgggaattcactgcgggatttgttcagttcagggtatttaataacgagagagcagccaacgccttgtgtgctggaatgagggtcaccggatgtaacactgagcaccactgcattggtggaggaggatactttccagaggccagtccccagcagtgtggagatttttctggttttgattggagtggatatggaactcatgttggttacagcagcagccgtgagataactgaggcagctgtgcttctattcta433 223623_atgagaagcacctgttccaactaagactaaagtggccgttgatgagaataaagccaaagaattccttggcagcctgaagcgccagaagcggcagctgtgggaccggactcggcccgaggtgcagcagtggtaccagcagtttctctacatgggctttgacgaagcgaaatttgaagatgacatcacctattggcttaacagagatcgaaatggacatgaatactatggcgattactaccaacgtcactatgatgaagactctgcaattggtccccggagcccctacggctttaggcatggagccagcgtcaactacgatgactactaaccatgacttgccacacgctgtacaagaagcaaatagcgattctcttcatgtatctcctaatgccttacactacttggtttctgatttgctctatttcagcagatctttctacctact 434 223754_atagctgccgggcaacgtgttgtgtaagtgaacatctgggaggtaaacactacacgtgaagagtggtgaaagggaacattgattactgaagtgccctggagagggaaagcactggtcaacatcacatggacaaatttcattgttttctaaagatggcctggaagtagtctttgccactgcttcctccacaaacagctcttcataacatgggctgcatgaaatcaaagcaaactttcccatttcctaccatatatgaaggtgagaagcagcatgagagtgaagaaccctttatgccagaagagagatgtctacctaggatggcttctccagttaatgtcaaagaggaagtgaaggaacctccagggaccaatattgtgatcttggaatatgcacaccgcctgtctcaggatatcttgtgtgatgccttgcagcaatgggcatgcaataacatcaagtaccatgacattccatacattgagagtgaggggccttgaggctgtaggatgaca435 223952_x_atggggctatactccatccaaatatgcagtggaaggtttcaatgacagcttaagacgggacatgaaagcttttggtgtgcacgtctcatgcattgaacgtctagacaaactgaaaggcaataaatcctatgtgaacatggacctctctccggtggtagagtgcatggaccacgctctaacaagtctcttccctaagactcattatgccgctggaaaagatgccaaaattttctggatacctctgtctcacatgccagcagctttgcaagactttttattgttgaaacagaaagcagagctggctaatcccaaggcagtgtgactcagctaaccacaaatgtctcctccaggctatgaaattggccgatttcaagaacacatctccttttcaacc436 224009_x_atggggctatactccatccaaatatgcagtggaaggtttcaatgacagcttaagacgggacctgaaagcttttggtgtgcacgtctcatgcattgaaccaggattgttcaaaacaaacttggcagatccagtaaaggtaattgaaaaaaaactcgccatttgggagcagctgtctccagacatcaaacaacaatatggagaaggttacattgaaaaaagtctagacaaactgaaaggcaataaatcctatgtgaacatggacctctctccggtggtagagtgcatggaccacgctctaacaagtctcttccctaagactcattatgccgctggaaaagatgccaaaattttctggatacctctgtctcacatgccagcagctttgcaagactttttattgttgaaacagaaagcagagctggctaatcccaaggcagtgtgactcagctaaccacaaatgtctcctccaggctatgaaattggccgatttcaagaacacatctccttttcaacc437 224342_x_attatctgcggccccaggacagaaggtcgccatctcctgctctggaagcagctccaacattgggaataattatgtatcctggtaccaacaactcccaggaacagcccccaaactcctcatttatgacaataataagcgaccctcagggattcctggccgattctctggctccaagtctggcacgtcagccaccctgggcatcaccggactccagactggggacgaggccgattattactgcggaacatgggatagcagcctgag 438 224352_s_atttttatttcaggcttccagctgtccctgtgagttatcctggacatttcgatggtttttggtaaggccaaactctgataagcaaaacagagaatactgacggtatacttaaccatatgtgtaactgatacttggcaccatggaatttttcattgagttatttcctcattcttttaaaaaataagggactataaatcagttatttagtatcttttgtttttgtagctgattccttaactttcttgtatgcctctagtaatttcagagattaaatattgctttaaactgtgatactttgatttgctagattgacaaaactgatactaatataattaagttcatctttgaaatacatctttgtgcgtagagccaaaaaaagagataaaattaataatagttcacttgttatttgagattaatttggcatttgaaatgatcattttattttacaatcatttataatgaatcaatgttccagttagctttaaaaggtatacggtgctaattagtaaaatattgaaggcaatattttactgctagcttgca439 224412_s_attaatcctgacattagctgacttgctagtgagcttgctttaaaaatctacactcttgcattcttaggcatacaggggaaatgttgaaaaggaaggtggaaaaccaagaatttagtttgccaatgattgcctctgattcttgtaagtttgagttccacaagggctaatttattccccttttacttgggttttggggtggtggaaagcgggaaatttgggtgatttgttgattggcaatgaggataaaatgttaatacttttttggggacttaacaactttatcctattctacaagtcagtaaaggaacaattggtactcacctcagtgctgcactcaactatggaaagaggcagagtttgcttgcccaattgccaaactaaa 440 224480_s_atattagtgtcattagtgtgttggaagagaaatactattcagtaagcttcgccaaagaaaagtgagtcaaagttaatgtgtgtgtgcatttatatgtaggcagctcgtagaccacattttagccagcaactggtaacaaagagcttagttttccttgtttgaatgctgtagatctgtacctagtacccctcccatctactgatttgtttgtttttgtaaccaaacacattttcagatagaaggagccttaaaaaaaaaaaaatcacattgagtaacttcagtatgaatgaatgagagtgtgtggagctacccctcaccctccacccctttgtgctttttattcccgaattttcccagtctcttaaacagaaaaatgactgatataattatcttttggaaactgagccttaattttttttagagggggaaataagttttccccaactcacacagcataagcaatgtttgacagcaatataatgccgttgtaaactactgagagtattgtatctgttctggtaaccatgtaca441 224560_atttgtttttgacatcagctgtaatcattcctgtgctgtgttttttattacccttggtaggtattagacttgcacnttttttaaaaaaaggtttctgcatcgtggaagcatttgacccagagtggaacgcgtggcctatgcaggtggattccttcaggtctttcctttggttctttgagcatnctttgctttcattcgtctcccgtctttggttctccagttcaaattattgcaaagtaaaggatctttgagtaggttcggtctgaaaggtgtggcctttatatttgatccacacacgttggtcttttaaccgtgctgagcagaaaacaaaacaggttaagaagagccgggtggcagctgacagaggaagccgctcaaataccttcacaat 442 224663_s_atggtcagatggtcaacttttttcagtattatttatagttggcacttgattgcagttctgtgaggcttgagcattcatacacctcacctgccttggcaagcctattttagtgatatggcagcacggatataacactatgcattaaaagcactttttgtaataagtttaatatcctaaaaggaatgccaattaagttttgttaactgtgtcatcaacttatcctagtacctcagtgttcattcctgttacctgcatatcttcttaaaagaaatagctgttattaatgcctttttgttttccattgagtgtacactactgaataagtgtaggagttttatgtttaccatgtgagtcctgcaacactaaagatattttgaatatcagtcatgatggcaatttctgtataaaagagccttaaatggaacattgttttgagatcaaactccccaccc443 224694_atgatatctggccatgggtaacctcattgtaactatcatcagaatgggcagagatgatcttgaagtgtcacatacactaaagtccaaacactatgtcagatgggggtaaaatccattaaagaacaggaaaaaataattataagatgataagcaaatgtttcagcccaatgtcaacccagttaaaaaaaaaattaatgctgtgtaaaatggttgaattagtttgcaaactatataaagacatatgcagtaaaaagtctgttaatgcacatcctgtgggaatggagtgttctaaccaattgccttttcttgttatctgagctctcctatattatcatactcagataaccaaattaaaagaattagaatatgatttttaatacacttaacattaaactcttctaactttcttctttctgtgataattcagaagatagttatggatcttcaatgcctctgagtcattgttataaaaaatcagttatcactataccatgctat 444224823_atgacctaatacatttcctctgtgtgtgtgtgtaacattccaaatactttttttttcttttccactgtttgtaaggtgcaacaatttaatatttttaagggactttttaagagttccttaagaaccaatttaaaattacttcagtgcaatcctacacagtatcaacattagaattttgatattagtcttatgttatcttccattctatttttatctgctttttgctgctagtttcaaactgccagtatttttccttttgcttttaaaatagttacaatatttttcatgatagccacagtattgccacagtttattataataaagggtttttatttgatttagcgcattcaaagcttttttctatcacttttgtgttcagaatataacctttgtgtgcgtgtatgttgtgtgtgtgcatgtgtggcgtatatgtgtgttacaggttaatgccttcttggaattgtgttaatgttctcttggtttattatgccatcagaatggtaaatgagaacactacaactgtagtcagctcacaatttt 445224836_atgagtgagtcccagttacatcaaacagtgacttccagttattccccagtaagtctgagtggttccttcaagctgggtgtctttccagcctttgccagtctagccccagcagggcaccgtgtatgaatgcagtttggtgctgttttagagtatgcctgctccccagccccctgcctggaaccctctgagcaacttgctctgacctataatgtcttaggtgcaacacggaccccaccagagctcttggatacccccctagatccatgtggctttatgtgaggggactgaatgcagacacaccatagcccccttctactactttccctctcgccctgccacctagttccacatggaaccaacaagttgagtgcatccctgttgggtgttttgtgttgagactggctgaaatgaggagactttgaccatgtgacgtgtcaacagactcaaggagacaaccacctcaactgggtcatgtg 446 224840_atccccagtctcacctacgaaatatgaagagcaaaagctgattttgcttacttgctaaactgttgggaaagctctgtagagcatggttccagtgaggccaagattgaaatttgatactaaaaaggccacctagctttttgcagataacaaacaagaaagctattccaagactcagatgatgccagctgtctcccacgtgtgtattatggttcaccagggggaactggcaaaagtgtgtgtggggaggggaagggtgtgtgagtggttctgagcaaataactacagggtgcccattaccactcaagaagacacttcacgtattcttgtatcaaattcaataatcttaaacaatttgtgtagaagtccacagacatctttcaaccaccttttaggctgcatatggattgccaagtcag447 224959_attcatgcgtcatccctaaaataataagatacatgggatcaaatagcccttgccttttcaacacaaatcagttggaaaattatggtttgagtcctgttgctgccatggcttctgtttctcagaaatgagtgtgtatgaacataccaatctatgtaataggctacctttttttgtcttctttggaactttgtacacaaaccaagacaatatcagggtgacaggtgaatgaacttaaattctcagtcttgtctattcaccaaaaaagtatactgcctgttttttctttaattattcaaggttgatgacttttaggaacatgttttatactgtattttttaattaaagcaagtgccttgatgtaattccatgtaaatcattgcttaaccctcttatgggatgaggatgagttattaatgtattgcagcctactggaaaggagggggagttggttaatagcagatacttttcttctagaagcttatgttttatgctgtttattatgtaagatcctgtatgtgtgttgaga448 224963_atataatgatccattcgagttctgtgatccttattgttcttaattgtgtttctctacgtattgttacagatgagccatacgtttctttgtatcaatgtagacatgacttcagatacctctgaggacctacccagcagtctaggaccctgggccaagtgctgggactatggtactaaatccagtagatgggctgtgtagcaactctcccagggaacacactagggtacttagggaggtgctttgtggagcatgttgaagctttgagatctgagcaggaggcagtgatgtccctggtctattcagggaaagatttcagtgtgaaatggtaaacatccaattgacaggatttagattttgcttagtttttctgctttttaatgtttctatcccccatctcagtgttttctttatccatcccagtgatgcct449 224964_s_atataattttacatgatcctcaatatcaactccagtttaaaaagtgttatttttaaaacatttgaaaccaagtactgtttaatttcaatcagaagatgcaaatacatactttgatctatgtttgattttgctaataatatttgaaggagattgcctaccaaggacaaaacaataaatttaaaaatcaaacgatttctccatacgctcatagtcacatatggaattttgagaaaataaagcatgctgtctttaggaatttttatacttctttgtctttcttccttaatatttgcttctagctgctcttggcaatgatgaattgttatgtatgcattaatgttttgcagcccaaaagttgttcacatttttcctatataagatctgtggagtgtgtgtttcaaagagagaactacagaaatgttaaagcaggaaaacctgaatgtgatgtgcacattttcatcccacatggaca 450 224989_atcatttctgtcacatgcacttagttgacattacatctacatatattagctttttcctacatgagccatctatttacttagtaaccagtgttcttaatgaagtatttagtcttgggtttcttgtaaaatttctctgcattccttagacagtgtactatacatgaaatattcttgttgacctagtaatttatattattccatttaattcttaaacctatggcctttttattgagcacactcttaaatcattatttggcttgtaaacattcatctgaattgtggctacaatcctctttaaataatctaggaaaaaagaaagataaagcttacattttcacagttttggctcttaaacacattccacaaatgccattaagaatttattttgttttaggccagtcatggt 451 224990_atgagcttctagaaatttcacttgcaagtttatttttgcttcctgtgttactgccattcctatttacagtatatttgagtgaatgattatatttttaaaaagttacatggggcttttttggttgtcctaaacttacaaacattccactcattctgtttgtaactgtgattataatttttgtgataatttctggcctgattgaaggaaatttgagaggtctgcatttatatattttaaatagatttgataggtttttaaattgctttttttcataaggtatttataaagttatttggggttgtctgggattgtgtgaaagaaaattagaaccacgctgtatttacatttaccttggtagtttatttgtggatggcagttttctgtagtttnggggactgtggtagctcttggattgttttgcaaattacagctgaaatctgtgtcatggattaaactggcttatgtggctagaataggaagagagaaaaaatgaaatggttgtttactaattttatactcccatt 452 225207_atttgtgtgtaatttcatggtggcctagtgttgtggtgcttctggtaatggtaatagaagctcaactatttttttgtggatttcagtttttatcatcagaagtcctagacagtgacatttcttaatggtgggagtccagctcatgcatttctgattatacaaaacagtttgcagtaggttatttgtcatttcagttttttactgaaatttgagctaaacatttttacatgtaaatacttgtatttaccaaagatttaaatcagttgattaattaattaactcaaatactgtgaactatctntaaaacactagaaaaaagaaatgttagtatctcaattacaccaactgtgcaaatgaactttgataaaatagaaataatctacattggcctttgtgaaatctggggaagagctttaggattctagtagatggatactgaatactcaggcccacttaanttattaatgtatacattgtgtttttgtctttatgctatgtacag 453 225242_s_atggcgtgcaattttggtctgcgccacataaccattctgaagcttttaggcgttggagaggaagttgggggagtgttagaactgttcccaattaatgggagctctgttgttgagcgagaagacgtaccagcccatttggtgaaagacattcgtaactattttcaagtgagcccggagtacttctccatgcttctagtcggaaaagacggaaatgtcaaatcctggtatccttccccaatgtggtccatggtgattgtgtacgatttaattgattcgatgcaacttcggagacaggaaatggcgattcagcagtcactggggatgcgctgcccagaagatgagtatgcaggctatggttaccatagttaccaccaaggataccaggatggttaccaggatgactaccgtcatcatgagagttatcaccatggatacccttactgagcagnnannnnnnaccttagactcagccagtttcctctgcagctgctaaaactacatgtggccagctcca454 225269_s_ataactgtgtacttgtctggtcagctgtgtatgatcagttatctacctcagagtctattttcttttgtgctgggacaggttgctggccctccctgtttccacagaccaaatcctcctagctcaggagctagggctaagcagttatttctttcaagtattttttagttcttaaattttatgcttgtatttgatgatagatgtcagtgacatttcatagtttcaaaagtccttgctgctctgagaagtgtagattctagtgaaaattacatagtcataagagaaatgtgtttttgtttttgtttttgtttcatttttttaaagttgtggtattattggttctatgctccctggaatattactgctttgtgaaagtccagactgaacgcagcaccctctgtgtacctagtacagttataaacctgggtctctcactacttgatatttttgcattagttaagacagaaatttgatagctcggttagaggggaggggaaatctgctgctagaaatgtctgaactaagtgccatactcgtctgggtaagatttgggaaacataacctctgtac455 225275_atgatgagagcaaaggggtcgcaccatatggaaatgttgaaaactattgtaaagtagtattatgaagtagcttttgtgtcattcatgtcgatgacatgaaagtgaagtaaatttattctatgtaaattcacactaaaaccagtacagtaccataagtagaatacatgtaagaatcacctagtcttcactatattgagtaaatataacatgctaattttacaattaatgaaactaaacttttaaacatctccattatatctacatccttttgaaggtatttatcatagttgccaattttaattttaggattgactttctctttctgaatgacttcataaagtttggtgtgaattttgaagacttgggttactaatgattgtatctttgctagtcaacaacttatgaaatatactcaatgcgtctgatgtgtcattaagtgcagaaataactaagacacaaataacctttgcaaaccttcaagctgtgtaatattccaatgttgtttttttctttgtatatatacttatatcacgtaggatgtaaaaccagtatgaccttgtctagtctccaaacttaa 456 225353_s_atgccacacgtccaaaaccaatcaggtcaactcgggcggtgtgctgctgaggttgcaggtgggcgaggaggtgtggctggctgtcaatgactactacgacatggtgggcatccagggctctgacagcgtcttctccggcttcctgctcttccccgactagggcgggcagatgcgctcgagncccacgggccttccacctccctcagcttcctgcatggacccaccttactggccagtctgcatccttgcctagaccattctccccaccagatggacttctcctccagggagcccaccctgacccacccccactgcaccccctccccatgggttctctccttcctntgaacttctttaggagtcactgcttgtgtggttcctgggacacttaaccaatgccttctggtactgcc457 225381_atgtatgtttgtaagtgcttctgcacgaatgtttatacatgactgtttccatagtacttatgtttttaaaaatattcagtcatttcctactataatcctcatgtatccatgtaactgactcaaaaatacttcagccacagaaagctaaaactgagcaaatctcattcttcttttccatcccctttgcatgtggctggcatttagtaatgattaataatatggccagctgaataacagaggtttgagacacaattctttctcaaaggagtcagctaagctgggtctacttatggacaaacatctaaatgtgtggaagtatctgatatttgacaatggtaaatttccacttagctagctagcattgtcagacttcaatctcctcatggctctggccgtcctgttttaagcatgataattgttggccacatctcacatagttctcattgagtgagttcataaataaacagggtttttttttttttttaaagagcagccaagcacaaagtgtgactttgttgacattttatgtgactttgtcatatgttcctaacc458 225442_atagtgtcaggtgccttgcaggaaaataatctgagtcccaagctagcctgtgctcatccacaatcacaatgaacatgtcaaggaagaatttgcagagactcaagggaagcacaatgggataaggtaatcactttcagtgaaaaactgttttcttgaaaacaggcttggacacaattgaaagctggcttcctgcaaacacaccaagagtctgtaatctagcctatccattatatgtcctttattattcatgatatcctattcttctaccttgttgcctggtaactttttctgaggactgagtttctgcagcgatgtggtgcactcttcctgtgatgaggaaacatctgggccccct 459 225458_atctggacacccggttaccaaagtcagcaaagaagatgcggtaatcgccgcctgatctccacatggtgaacacaacactcccaccaacacctccttgactggtcggtcttcagcaccgggggtgggcaggcaggtgttctgtgttgacgagaattgcacaggctaaacacaaacacggaaccagagtgagaacacctcactcacggcagcccaggctgctccctaccaggtgacggagcgcgccggggctgtgggtgccaggggctgagtgctagggactcgtcatgagtggggatccccacgttcctgtcactgctgtcaaacagaaggtaaacagtcttatgaatgtatttccttaggaaaacttgtaaaaacttttattaggatatctatttaatactgaactttggcctactttgtgatagactataaacaaattgaggaaatcactatttctcacttctgtattttctcaaaaataattttgttacagagttcaatatactgtgtaccattgatcttctattgtg460 225575_atgaaactgcggatcccaaactgttccctttttcatttcttgaaatgttaccactacagacatttttttaaggtgaataaacagttgtgatgtgctgtacntaaaatcatgtttaatcgtataaggaaacatttcaatacacttatacaggaagaaaactatagatgaagtacatgtgtgtgattcagtctgattcacagaattctgagagtaatatggaataaaacaactccacttagatgataactgaagcatttcctgccttgtgaaaatttggattttaaattgctgttagaatgggaaatttggacactttatatcattgtataatttcagaatttagtttctgtatcttttggaaaacatgattatagcaaaaacatagaaaataatctattactaaaacaccataaatgtaaaactagtatgcttggctgttaactctaaagatgttacttatgtctgttttta 461 225602_attgagggtgagcttactcagggcccccagaggaagccctcagcctctgccctccccccacacagggcgggagcccaggcctgttcctggcagctgtggctgcagctgtgctcctgctccctcctggaatgtgcgacaagcccaaatgttccngggnaggcggccggggcagggggcttagaagtgctaatatggttctgtgttttgcctgaaacgataccaggttcccctgaatagcaactttacaaggtccatgtgggagggaccaacccagatgccctgctgagtgtccctgaaaccatggcagctccatctgtcaagatggcaggggccggagtgagggggctgctggcttaacagcaggcatctgggcaggccagtcctcaaagcagctcctgaaggtctgtgttgcactgtcaccagtctcaagctatgcctctaatttcaccagggatattg 462 225604_s_atgtgtgatgcatgtgagcgtctctggcacacacacttggacatacagttctgtgtgcgctcattcttattacaggagtgagcaaaggaagcatttaccccgatggttacctagaccacgattatttggattggggggagg 463 225626_atatccctgtattcatggcttgactttgtgactgctctacactgcatgtctgacattgcagagtgagctatgttgaggtaaactggttggttgtcattattttgcaatcagcctggtctctcccatgaagatgtcgtgtgcataagcacaatcatcactgattagaagatcacagcagaatacccttggattagagagaagttcgtaccttgcatttctctgaattctagtctctcataagcactgctttgctggatgattttcactgctttgtgttaatgactttgagcgatctctcacatgatggggttctttagtacatggtaacagccatgtcatcttacacacctagcattgtgaatgctgtagtgacatcctttataggcaccttacagctcaaaacttttgtttcatttcatgccttacttatca464 225688_s_atagtgccatttattctagtttatcatgttttgcatgtttgaaagtatgaatgtgctctttcctaaaacatggcaaatgaatagatgtagagaataacaatattacttacaagatgaaatgattagattagaagtgtccctttattaaactttgtcagcctgactgggtacaattcttttgttaatttgcagtgtggtttgtatacacgtatacgtgttatcaataataagattttgcaactggatgacacaagattttacttgaacagtgaaggacaaaaatcatgattgtggaagatatttttaaaatctgattttgcagcgatcacttttaaaccctgtagtgatgtaagactaaaatataattgctaagattttgttggttaatgtaaagatatgacttttctgcactgtactctcttcataggattgtaaaggtgttctaatccaattgcatgatgtagtaagcctcttaaatatgtgtgtta 465 225710_attcctatgtcttctttcttaaatccagttgctgattttgtaaaatacagttgtgataaagcagcattacgggggggaaaaagctatattccaactggtgttaaatgtattcaacaaaatcttacatcatacagtatttatttcttaattaatagaacttcagtgatatacttggtagatatctcaagccttttgtcttttacacaatggtgctctatcctattgttttcttttcaaagaagcatctgaacacttgcatttctattttcctatccaaaggcatccacatctaagtgtgtttttaaagttgattaaaattatttttctgttaaagcattctgaaagtgtttgtctttacctagaatgatttgtacacactcgtggtcaactgaacatgaatgtcagtagtagtctaattatgggaagggtaaacgtgttagattaaggctcttaaagctctaaaccatataaactatggacttgtatcatgatttaactgttcttagatctttcttacacagtgattcattcctctatttgtacagtggcttt466 225720_attatcaaaggtttgccagccaataaagtgcatcccaagtatacaggggagaaagctagactcctacagggtcctagagtttaagtaatttttttgttattaatataggtaataatttttctaatttttattttttggttccaaatgtaaagctccttgtgtttacctctgtttatgtcattcttgacatgtttatctaaattatgtgtgctctgtgacaggtgaaatgtaaatctgggatccatagtcaagatatcataaggacctacttcccagcctacctttcttcctctacctgataatgataatactcaaaataacaacattcaaaggaaacacaaagaaatcctgctttcacatctcctatttcttgggctccttaataactactgatggtttgttcatgaaaaaaaatttttaaatcaaaagattgtacttggccctgagttgaaaaaatttcaaaaatcaaaagtttgtacttggccctgagttgaa 467 225721_atcagaaacatgaccctcgctggtcttgggtccacatatcattggactctgggggacacaaagatgcctgtgacactttggtgttgccgagttagtcaacaattattctgggaaaaagcagaattgaattcttctctagatgtcctaccagggttggccaagggccacaaagcaggctaataaattcccacaggatccagacaccaggcaaaattgctctaagaagccagttactgtcatccctctatggttctagaaaaaatagtacaaaaatgacaggtcatcctatgagcgtcatgccaatgaaaccccatcttctggagaagcccttgaatcagaattatcttttttcttgatgtcgtcagatgcagccagtttcttaatttttttaaaaactgtatgtttctgtggtatgtatatttgtacacctaactacctggcacttggaaatcacagcactact 468 225728_atttatcctgcgacaacactttcagcagantagcctctccttatctcacagatcacaagcacccctagatagtgtgattctgtcagatagcatttatgcaaaaatctatgaagttaaaagatcgtagaagccaaatgaaatgtacatatctactgactgatgacaagggaatttcattaggaagaaggtaaagaaacatcgttgagtagcctaccttgatttctgtcaagttcataaccagcttcatattttaaaggcttcaggtttgaaattaagtcaactgcatgcagctttgctgataaatgaataattctctttgatgccatttatgagaaaagacttcaatatctgttgcctgtcatatttaagaaaaattactgtttctactctctgtatctgattttaaaagaaaaaactattcatacctggcttccaggtaattgactttga 469 225782_atgaactgagtcaatatggcaaggtgtatgtgatctgtgggagttatgccatttaacataggaagtgcatgggactttccctctctgcactccagctcttactgtaccattagaagatgcagaattctgttggtgtgcaaaaagtatagccttacattcaagcagaatggatctgaagaaagcagcaatatctgttactagagaacattcccatgtgtttaaactcttcacttcttagatgcatttaaattcttaatgcaaatgacgtagcaatttgaaaacttctccgtattacttgtgtttaaaatgtcttgctttaaatacaaaacaaatggtaaaggggattatcttttgtttagatggttaaatattatttttgccttagatagctttgtaataatttttctccagacagttcaacacttttga470 225894_attactgactgactacaggggctgattgtgaagcacgaggaaccccatgtgtgtggagactgtagggtgagagcacacaattattagcatcatttctgagtgatctcacagattttttttcttgtgtttgttttgctttttgacaactgcttctcccacgttccttgcaattctattctctcaccttcactttactatttgtattcgatggaccaggataattcaggcaaggttaccttgtaaacttnaattggccacacaccatgttgtcacccagctggctatgaagtgaataatggtactgaaagtaaacctgaagacctttctcagatctattttaagtctgagtctgaccaaccatggaaaatattcgacatgaattaatgtagagaactataaagcatttatgacagctccaagaaaaatcatctactctatgcaggagatatgtttagagacctctcagaaaaacttgcctggtttgagggtacacagtaccattttaatcttctgaaaatatctgtattcctgctctttttctgctgtcactgtcaatctgctatattttt 471 225895_atttcctgacgggaatgttgtgctataatgaatctgcataacgcttgggattctaggaggaaggaaggttccatggacatgtaagtacagcatattcccctcagtcttctaggagggcagagtgaatcccagaactggtaagattgggaatctgagcattgccactttaatcttagaatatttatcattttgacacatcctgttttttagagaggaaaacaaacacagtttctgcattggtagtgtaaagcataccttgttaggaacgtgttttgtaagacacatttgggttgtcattctagagcatgtcaaactttgtacttcaaaatatatttagtatgattgttagtggtaacatatatcaaggctttgaattaactgttttatttaattttcacaagaagcacttattttagccataggaaaaccaatctgagctacaaatagttctttaaaataagcccaggttatttagctattctagaaagtgccgacttctttcaagaag 472226001_atttaaatattcattccattacatctagactcaccaagaactacatgttatgatgttaagttgaagttgaaacatgatgttttgcattaaatttaagatatgcaaatttatgtagagaaaataaatgttatataccctataatctttcacctaattagtatttaattatatggatttgttttatattataaaagatgttttgattttgtcttttgatattgacaaaattgtttggatatccttatgttctcaagtctgtatctgcctcccctgccttatttcttatgttttgccacagttaacccattgtgcttctttgtaatcaaacagtttgtgggagaatgggcttattgaatgtctaaaaaataagtttaaagtgtttgttaccctaagttttttacatttttaaactctaattacatatgtgaatgttattactctcagtgaattgttattgtttgcaaaaatgcactgggcagtaacattttgt 473 226051_atgccggactggaaccgtctgagcggcctaacccgcgcccgggtagagacctgcgggggatgacagctgaaccgcctaaaggaggtgaaggctttcgtcacgcaggacattccattctatcacaacctggtgatgaaacacctccctggggccgaccctgagctcgtgctgctgggccgccgctacgaggaactagagcgcatcccactcagtgaaatgacccgcgaagagatcaatgcgctagtgcaggagctcggcttctancgcaaggcngcgcccgacgcgcaggtgccccccgagtacgtgtgggcgcccgcgaagcccccagaggaaacttcggaccacgctgacctgtaggtccgggggcgcggcggagctgggacctacctgcctgagtcctggagacagaatgaagcgctcagcatccc $474.00 226084_ataatggcttctatgatcagaactgggaaaacagtgnatcttatggtggaagaggtnctcagcaagtgtacagtatttaccttcctttgtcttacatnggctttttaaattttccattaatttcaacataattatgggaacaagtgtacagaagaattttttttttaagatatgtgagaacttttcatagatgaactttttaacaaatgttttcatttacaggaaattgcaaagaaaattctcaagtgatagtctttttttttaagtgtttcgtaagacaaaaattgaataatgttttttgaagttctggcaagattgaagtctgatattgcagtaatgatatttattaaaaacccataactaccaggaataatgatacctcccaccccttgattcccataacataaaagtgctacttgagagtgggggagaatggcatggtaggctacttttcagggccttgacaagtacatcacccagtggtatcctacatacttctttcaagatcttcaaccatgaggtaaaagagccaagttcaaagaaccctagcacaaatttgctttgg 475 226103_atggaacctatcaatttgagtggactttttctttagtagtacaccatttnggttgtngtagtttcaaagtctttctgaagcagatatattgggattggagcggggtggggaaaactgtcactcctttcagaggaaaaggggaggagcatggagaaaaacaaaaattaaaggacttaaagaatggctatacagtgttgagtgttgaggatattaaacatgttatttttcaaacgtatgtaatatatattaaatttataaagcaaatttatgttgtgatcttgcctgaacaaattatattttaatgaaaaaactttctattaatagttcacgcaagagaaaacactttcaacatagtcgaaggcttcaagatctaagtgtatcagacttagggaaaaagtggcacaaccttcgatttaaaattctagtctttaaaatgagtttgtaaataattagctattacgttctattaagttgtt 476 226147_s_atagggatctctctacaagagcccctgcccctctgttggaggcacagttttagaataaggaggaggagggagaagagaaaatgtaaaggagggagatctttcccaggccgcaccatttctgtcactcacatggacccaagataaaagaatggccaaaccctcacaacccctgatgtttgaagagttccaagttgaagggaaacaaagaagtgtttgatggtgccagagaggggctgctctccagaaagctaaaatttaatttcttttttcctctgagttctgtacttcaaccagcctacaagctggcacttgctaacaaatcag 477 226302_atggtaattatggaaactcctcaaagaggagaaagtaatttttttccagacatttttctcattctgtgtctttcacacactagtttccatagttcgagaattctgttttttaccattgggctgtgaatgttcacaatatcagtcctgttgaattcctatgaggtaatcacaatgtgtatatgttcattttctaggtatgataaaagaatgtatggctttttattctgtggaagtaaaatcctgaacgtttacaacttttccttaacttgtaaataaaaaattgtaagttttttctttttttacagaaaacttagcttgtgtaattctgttagtttcagatttctctcctgtttttgcaaattgtgggaaagattgacaatgcaaatgtgtcaaagacatactgttgggtgc 478226303_atacatgggtttatacaagttcctcttgagaaggcaaaaagaccaccatgtgtgagagctctttgacttggccaataggggcctatcttaatgcacttgtttggacacatttctgatcttatttgtaaaggctgcaaaaggagaggatgaaatgctgtaaaagtaggaaatgaagtggaagctggaagaaaatgtaattggtggtacagctatgggccagatggtggaggggagggtggggacccctgccggcaagcagagtgtcacagctggctttcctcacttgggaaaagggtactgccggtctagcagcctcctctgtactcagccaggacacccagcgcgtgggacctgtttgtgtctgttttgcttccttgggaacggcacagtcactcaccctgccatttgcggaaatgacctggtgcactttgactgttaagcaatgcgttattgctgtagtcaaggttagtgcaagcaaggaaacattcccagtaaggtatttgtttccattttctgtctgtgcttctgtcagaaacttgctaggac 479 226304_atcaaacgtcctggactgcacagacctcccactccagaccatccaggcctggttcccaagacccgatccttcccctgcaaccagacagtctacaactgccccctccagcccattttctgccgtgaaaccccagccagccacaccagactctggaaccctttttcgactgccccaactcttggacaccaggccaactagaacacccaacaccaaactgtacagactctcccaccccaacctccccagactctgcacggatgtcctaggccccctccccaactctaaccagaccccatccccctaagtccctttgtcttgacccccaagtcttcaaccagatatcctcggcaacccacctcccaccctcctcctcttctccttcaagacccaactgagcacccgctctgattccccacagcctttctccctgccaccactcccttagtctttcccaggcttactctcccaataaatgtgctag 480 226333_atggtggagttggtggtcttaatttggagatgcaggggcaacctgtgaccctttgaggcaagagccctgcacccagctgtcccgtgcagccgtgggcaggggctgcacacggaggggcaggcgggccagttcagggtccgtgccaggccctcctcagtgccctgtgaaggcctcctgtcctccgtgcggctgggcaccagcaccagggagtttctatggcaaccttagtgattattaaggaacactgtcagttttatgaacatatgctcaaatgaaattctactttaggaggaaaggattggaacagcatgtcacaaggctgttaattaacagagagaccttattggatggagatcacatctgttaaatagaatacctcaactctacgttgttttcttggagataaataatagtttcaagtttttgtttgtttgttttacctaattacctgaaagcaaataccaaaggctgatgtctgtatatggggcaaagggt 481226430_atatttttccatcttattcaagtcagagcacttttttttaaatagcaatacaacaggcaagagaatactcaaaaatatttaaaactgtattgataccaagagtatgttttaaatattttctaataaatacttgagcggtttttgtctggcaggcttccaaatttgccaaaattaagcgttcagtattttcaacacatacgctttttactggtttatactgaactatctgatgagaattcctgtgttcccaaagcaactgatgtttacaggtcttgtgtttctcctcctcctttctaaggatgagggaatccacaacagactttctctagaaaacactaatgatggacaactttttggtgtcatcaatgagttggctactaccttgatgtaaaaatttgtaaggaaaattttcaccatttcgagtgtcaagtgtatttttaactgtctggtttgtacttttatgacttttgtactaccaaagcgga 482 226492_atagtgatctctggaagcgctaaagctaaaatttctgttcttgaaacacttcagctttgcaactaaaatattacagattaataataaattaaaccaaccaatgataaacactactcagtccaccaacaacaaacgtgtttgaattcaccttaccaatattaatcccagcgtgtgtaaaacagaacagtaactctatgtgaccccagataacattttgtaacattgtgcttccttgtagtttgtaatgtgagttcaatcagtatttatgttgaaatttctaacattaaatctagtctctatcctgttaatttaatttttaaatgctttatccatttgtgcaaaggtaaacgcagattgtatcttttttaatggtacggcataaaaagtaaccctcaagtgaagtgtctcta483 226594_attgacgagacctcttcaaaaacccacagtaaaactcccctccctccagttggccaccagtctgccaccaaacatgaacaaattctgctgctaatcggtttcccttgtgatctggttcctgaggtcttcggatctgtgcaatgaattatttattgttttattaaaccgacagtggtgtcccagagaggaaccataaataaaatggaaatctggtgctgtgataaagtaataactagcattaatgagacctggttttcctttcagaaagtccagtatacctgtaacaaaggttaaagcaatttatatttaatttgcattctgatgttaacatttaaacagcaattctaacaaaaatgcatcgagtctaattcttacctctatcaaaaaacaactgtataaatttatgaccaacattaaaacaaaaacaaaatgtaaattttctctttagaaatgattaactggaaatgagtgagacagcaccttgtgggttt 484 226654_attgctcgcattgatcatcctaatcatcttattcagcctatcccagagaaaacggcacagggaacagtatgatgtgcctcaagagtggcgaaaggaaggcacncctggcatcttccagaagacggccatcngnnnagaccagaatctgagggagagcagattcggccttgagaacgcctacaacaacttccggcccaccctggagactgttgactctggcacagagctccacatccagaggccggagatggtagcatccactgtgtgagccaacgggggcctcccaccctcatctagctctgttcaggagagctgcaaacacagagcccaccacaagcctccggggcgggtcaagaggagaccgaagtcaggccctgaagccggtcctgctctgagctgacagacttggccagtcccctgcctgtgctcctgctggggaaggctgggggctgtaagcctctc 485 226682_atgctgattctaattgtgtgtaggtcttgaggattaagcacacaaatttcacaaacttctgtttgagtaaacaaactcagccttctgtaaatatacatgcaagtttggaaacagtaatactgtacctataaatatatgctgtctgntttgtgtacagtatgtaaaaactccttttctgccacactaaaaatgcaagccatttatgggaatcctaaaactagtattgaactaaaactttgctaatgatctttattagaggatcgtccaacttttcacttaccttgggttttcttttcaattcactcttacactagtctgcttatttccagctgtttattttattgagtcctgaatttaaaaaaaaaatattttgattcattttgtaaatacaagctgtacaaaaaagagagatttaatgttgtcttttaaatactccaattttcattctaatatgaatgttgttatattgtacttagaaactgtacctttaatattacattacctttattaaaagtgcattgaacacatcaattttagatgtgctttatgtactgttatccta486 226694_attaagcattcagtgagctgccaattttgattttgtgttgctctttacccaaattattttttctttgtttttctttttttgggggaggaggggaaaaaagcagcaatactgtgtttggaaattatactctgtatctggttttcctgtgtatgttaaccacttaaatgttattatcctgctttggttttagagtgattgtgaggcattcaatgca487 226811_atagtgcctaaatcttgtttacctatcactttaaaaaaataattgaagtgtaagctaaataaaatgcttggagtttngcctgggctagtgagagttggtgcaaattcttgtgtgtgtttgcataggaaggtgagatgaccatctactaaagaggaagtagctaaatacagatctgtgggtgtttttaaaaaaactcaacctatctggtgttttattttaatggataaaaatgtaatttttctaaggtagcaacttatttccaaattaatatagatgaaaaatagataccaattagactaaattgaaagctttttgttctatatttgcatagcctttgaaatatttcttagtgcctaggaggtctggggattcctctttcgtggtggtcactaaccttacttgatgcaga488 226818_ataacaccaattatgcaaactacttttttttccagcagaaagggagctgacatgatcaaatccatgttttcaaatgaactgaaaaaggcatccagcaccacttatancacatttatttcagttccaggctgacagccntggggnatctagcaggatnnataattgtcatctggtgagagttgggactttgctcaattttaataccaatctctcctgattgtaattacctccactactttcatgatccccctacaatatttttttaaatgatatatttattcactgaatcaaatgtcattaatgagttatcttctgtggaggatgactgttctctttgttaatgttcacaatcaagatcttgggctgagaagaggcccttcacccaaggagtttgaagtatcacagcgtgtgggaaggtgggaaccaggatacccattcatttccaaccgagacacagagaagtgagtcacagaatttgagccngctctcttgactgcccagccagagacactgatttctgtaacctcttcacttgatcctgcctcttaagcatta 489 226834_attcatttctagagtacctgagccaaacaaatacacaacggaagctgcagctgtatcatcactagcaatttgctcatcattatttactacctttgaacctaaggtttcctgcctatgcttttgaaagcaaaaatcagtctcctttgcatgaaaaagagccttagatttttaaacatgttagttaccagaatgctaaaataccagttgattacccaaattattttggaaatctatccataatggaagtctacaacaaacacataaaacagattacactaagagctgagaaattcaaaggaactgaagattctgagagataaactgttcaagtcttagcaatgatactgcacttctctttgacaggttctgggcttaagttagaggccctactggttccaaaccatattccactgactttgcaag490 226841_atcctctgagtgttttgtgggttctgggtgttttgtacattttagccaagctaaccacttgtctgcaagtactgactttcctatgaattctttgaagattattgagtcagaaaggaaaaatatagccccaaattcccaggcttttaatgcattacattaactgcctattgaaatgagaagttcttcacaaacttgtatacccactaacaagattgcacataaacatgcattaaagtatatactaagaaaccctctgtccaacggctcatgcatatgaagtccgaacatgggagtttgccaattgcattcatcaagtcgttttgcggagtcagatccctgatggaagagctcacaggctctgccttccaagtcctgggttcctaactggtgaccttagcctggggtctgtggggagaccaaccctggcttccaagaaaccacattccatggactatcagaaatagacacagatttgggtgacaaagctggctctgtatttgcatttt491 227006_atgcaagcgcgtgctgagcaagctgcagtctccatcgcgggcccgcgggncagggggcagtcccggggggctgcagaagcggcacncnngcgtcaccgtcaagtatgaccggcggganctgcagcggcggctggacgtggagaagtggatcgacgggcgcctggaggagctgtaccgcggcatggaggcagacatgcccgatgagatcaacattgatgaattgttggagttagagagtgaagaggagagaagccggaaaatccagggactcctgaagtcatgtgggaaacctgtcgaggacttcatccaggagctgctggcaaagcttcaaggcctccacaggcagcccngcctccgccagccaagcccctcccacgacggcagcctcagccccctccaggaccgggcccggactgctcacccctgaccctcttgcactctccctgccccccggacgccgcccagcttgcttgtgtataagttgtatttaatggttctg492 227052_atcactgttccatggtcagcaagtcatatttcataatgtggattttccaaaataattattgaatacagctattctatggctacttttagtgtttttgtggtatgtggtgtgggagtgtttatggaattaccagtatcttaaattttcaaaggaaccttggaagtctatcactctaaatgaaagtctgtcactctacatgaattatgtgctcaaatttgaccaactcagtttaagacacaaaacagtaatttgaagaaggaaaaatgaagagagtttctagtttaatgggttaaatttttgttgttgcaatagtaagtttagtcttcttataatatttctaaatgaaaaatcataggtatttgttaccatgtgtgaagattantttgttaaaagcaaaagtggtcgtgtgatatgctaaatgttaattactgattttatatgtttaaatcacgccaaacaaattatgtctgtgccatccagggtctgttgttaatctttttctgagtacttggattgggataaagggcttgtactatgcactt493 227061_atacacttatagtctactgcccatgtaaggatcagctccggctaagaggccaaagatgggtgacatcgttatgctctgccntttattttttctttcttacccacttagcttcctaattggaggaaggaggcgtggtaaaggtatatgaagactatggtttaattagaccagaaaacactgtcataatctctggggtcatcagaatgtccagttttgtctttgggccaagataagggcagtgggatttatgatgtgttgtttatagtctgaaactactctggtgatcanccagggtcagtttctttaatgatggtttccaactggcctaatacattaagtaagactggctgataacatgaccagacagacataaagaccctgttgggaatgacattgaactctcaaagtcaagatttcttacacaaatctatcagctggagaaaatgaaggcagtgtggtatatgtgtgcaaataaggacattatgaagcttaaatatggaatgtctcttggacccccgatgtcatctgtattctctttttcttcttgtactatatcctttgcctgtaaata 494 227099_s_attcccagtgcgaactctgctgtgagtgtgtgcggggaggcgcgcccgcgctgagtcggcggcgggtagccactccatgcccttgtccgatggtttgcaactccgattttgcacaccgctccaccgtgccccccagcgcacacccattcacactcacgccaacactctcgctgaacacttttataattgttaggcgtggccgttgggactttgggcgcagcgcggctgctactgcgtctggaggattgatatttatttttgcattgcgatggctgaaggcatttatttaacgatctttttacctggatatgtctgtgaggctcctgaa495 227235_atgtgaagtaccatagaccatattgtctagatgggacaaaataataaattttgactaagaacttactgtttagagagaaaaaatagtaaataatgttcaaaatgagaagacaataactgacaagtctgtgatttttgggttagatgagaccacttttgatttttgaggaataaaaggagttagttttttggtcctgatgtgtaaaatgattcatggggtttcacatacagacaagtagttttcttttcagcaaatatttaacatatctctcaatatatttttcaccagtttttggtaaatatgcattgctataggtataccaagttttttttgttatgtttagtaactaatttcattttttctgtatatgtaaatatagctattggaccctgcattgaaaaccttcttagtactaacaacactccttttattattaccttcatagttactttaaatgacatatttatttcgagttttacttctggctgagttgcaaagtctatgagaatgttacctcctgtctcagaagcttgttagttattgtgccacc496 227265_atacatctgctagaaccttttgccttaactattcaccaatatatgctaatattcataaatatggattgactgtttacaaacattagaatcttgtcttggttccattttgatggctaatatttgttatcttaattaagactatttctgaggtcatgattacttgaaaatattgactaaaactgggtccttagaaattccaggtggagctgatttacctatgactgaggggaaaaaaaaatcaaattttactgataatagtaatgctccaaatgaattaatgacacatctgttcaataaataaagagcttaaatatacaaaacataagaaatctgggcaacaaaacttgtggtctttacttttgaatagctacccaagaaaaggttttaaaggtaaaagttatgagtaatgtcatcacaataagctcttgtttaaaattcttttcttttatgtataattaggtttatgtttcatgtcttt 497 227404_s_atatcccatgggcaataaagcgcattcaatgtgtttataagccaaacagtcactttgtttaagcaaacacaagtacaaagtaaaatagaaccacaaaataatgaactgcatgttcataacatacaaaaatcgccgcctactcagtaggtaactacaacattccaactcctgaatatatttataaatttacattttcagttaaaaaaatagacttttgagagttcagattttgttttagattttgttttcttacattctggagaaccgaagctcagctcagccctcttccttattttgctcccaaagcctcccccaaatcatcactccctgccccccttaaggctagaggtgagcatgtccctcacaattgcacatgtcaagccatcagcaaggcgcatcacacaaaaggcaccaag498 227522_atcagtgagtcgaggttgcgctactgcactccagcctggacaacagagggagactctgtctcnaaaaaaaaaaaaacctacagctgttcaaggaccagctgacaggtcaagtgtggccttttctggtctttgaacacatcatagaaagtgacaaatgctgcaaagccatgaagaacatgaactataaacgggtagactaactgcccagcttagacacttatctatgccacaaaacagctgaatttgtcacatttatatattgcaatatgggaagtattgagatcaaaacaggattccattgacctaattat499 227529_s_atgccatcacagttgcgattccatgagtagctgctttatgactgctttttgtactatctggatgtgcccagagttacttctgtacaagctctgtatctatgtccgttgagaacattattttaacaagaagaacaccaacagtagcatgaaatataatactgttttataattctaaagctgctgttaatttatgaagtacataataatctaatgtaaactgcagaagtcagagcaa 500 227561_atgcaaccattggggaatgaccttttcatttcagaagtggatgaggaaggtggtgtgagcatcaggtatattnctggaccatttcaagtgctggtgagaagaaaggaactctttgcctgaactgggcttggttttccaagtgctgctttggaaatgaagacccagagatgcagagcttatggtagttcataaatcttcatgttctattatctttcatctgccaataaagttcattttcaataatgtccaccattgctgtgcccagaataaccacaggcaaacatcaaaacaatacgcataagttagacaagattaaatcttgtctgatatctgcacaaacagatatgcaccatgttggaaacatgtgttttcctagtcccatccaggcttcccacaagaaagccatgatgtgggtctaaacc501 227623_atattgtttcccatagcagaatgtcaatattcacagtacatttctgtaaagagcaaaccaatataatgttttgagtgttgaaaaaaattccagatttntgaagaattagacaactcttcatctaccttatttctagttcacacagttatctcaaattccactgaaactaatgggatactgtcttgtgtagatgccagttgagtttataatgtgacctagtaaagctgtcttttttgttgtgttgtatgagtgtcggatcatgcttttaggaatacttttattaaaatggtgtgcattcatgcaaaaggccaactggcttttgtgaacaatagatcttttctcccctttattttgttctcttgacacttttgtgaaaattacctagcctgata 502 227662_ataaagccttccctaaaaagagagcatgccagtcatagagacactaatttggcacttttcctccttcttaggtttaaatgttataccaatgcatgtgtttgaaatatccattaagatgatttaaaatttgtcttgtattttgagtttcttaaatgcgtggattcttgttcatttatctctgaatatgtctcttttatattttggcacaattatacacattggaaagggccaacctattagggctcaagtatgtatatgcnaaaaaaaaaagttatatcaaacaggcacagttattacaactagagagaaattccagaaatatttgtttttttaagagaaagtaaattttcacattagatttctattcaaagtactaatatctacatggtccacacttttctattttaaaaaattgtgttctcttgttaaatagattaacatttccacttctgtttatcacaa 503 227682_atatctttccatattgaggacagcctctgcatataaaaatgttcattgggagaaaaattatttttaaaactaaatttttatagtagtcctccattactggcaattaaggagcaacccacaaaatgtcattatgtggttctttgattaggcataaaaagtattgcaaacagcttttctattcctttggaatatgaatctttttaatgtctaaagttaacctgcaacattttctagtaggacaagtcaatgtaaattaggtaatttttgcctgttttataccttctgtngcattttgttcaaatgaaaacattttttaaaacatgattgaattttttacttctcagataattggtttgagtgtggaatttcttttttaacactttgatatgtaagttagtgtaaattaatacttttataacactactaggctttatatttttatggaatgttttaaaatttgaaatttttgaantgttaatttagcagtactttatcattatgtgccaatactgacaag 504 227705_attttactccagtcattcgatgttgctgagatttacatatgactcttgtcaacatctcatcttttgacccaatcttattcatttaataagaggtctcattcatttgcatggaaaaatgctcattgtatattgcaaagtgaaaataacgagttgcaaaacagtgtatacatatatgtgtgtatatatgtacactttatttgtacatttctatgtgacataatgcaaaggaaagtgtctgattttattatacaccaaaggttaacagtgaatctctgtgtgatctctttttttttctttttgcctatctgcatcttcacttgccaaaaaatgaatatatgtttatgtgtgtatattacttgtgtcacaaaaaaccctaaagtagacagtaaaagaacttgtcaatcgcctttggaaggcaatgaaacacttaataaactctcaataa505 227725_atagccaagaactgaccggggccagggnctgccatggtctccttgcctgctccaaggcacaggatacagtgggaatcttgagactctttggccatttcccatggctcagactaagctccaagcccttcangagttccaagggaacacttgaaccatggacaagactctctcaagatggcaaatggctaattgaggttctgaagttcttcagtacattgctgtaggtcctgaggccagggatttttaattaaatggggtgatgggtggccaataccacaattcctgctgaaaaacactcttccagtccaaaagcttcttgatacagaaaaaagagcctggatttacagaaacatatagatctggtttgaattccagatcgagtttacagttgtgaaatcttgaaggtattacttaacttcactacagattgtctagaagacctttctaggagttatctgattctagaagggtctatacttgtccttgtctttaagctatttgacaactctacgtgtt506 227727_atgggctgttccagagattcgatcctcttaaggcattatcagtgagcaaatgtgaaggaaatggtgtctggaagaaagttctggttcacatgccttgtagctaagtctttctgcaaacaacctcccttccccccgtcgagtcatttggtgactttgatggggggatttctggttatgtcaaggctctggagacaggaanggcctttggccgccttggtagttgacctgccttttctgactccgggacgagccagtcctaggctgcctcngggagcacttgaggtatcccgcaggccatgaggacccactgggcagctcctggacagcctcttggctccagcccccacccgaaagtggnacactgnntccgccctggccacctggggactggcactgtggtgcacagtggcccaatgtggccaacggaagtttt 507 227735_s_atcacaggtgtagcactcccaaagcaagactccaganngnnnnnnacctcatgcctggcacctgaggtacccagcagcctcctgtctcccctttcagccttcacagcagtgagctgcaatgttggagggcttcatctcgggctgcaaggaccctgggaaagttccagaactccacgtccttgtctcaattgtgccatcaactttcagagctatcatgagccaacctc 508 227736_atcaccatgaccggtcacagctacaaatccagagaccatcaatcctgctagagtgcagggnggcaagcacccaagggtggctgaccaagactgcagagtctcctccatcttcaggtccattcagcctcctggcatttaactaccagcatccagtggtccccaaggaatcccttcctagcctcctgacatgagtctgctggaaagagcatccaaacaaacaagtaat 509 227826_s_atggttagattccgttttgactgcttggtatctcattgtaagcatttcccagggacactacacagtctttataattatgatcactacatcttttggataacttaggcttttgcactattttgtcacgatgcctcaaacttttctatcattgtctgtaattactcctataatcttttatt 510227827_ataatatctcaagatttctaggcattttcctatgtctaatagtaggatgttctctctgaatttatttattacaaaaataacattacaacaataaagcaaaataatatttaaaagaaagaaaaaacaaacagtcgcaataccagaacaccattgtagtcgtttgtgtatgtgtgacttctttactgtgttcatgcagagacaagctttgtaatacctttgtaactactgtacaggtgcgtggttagattccgttttgactgcttggtatctcattgtaagcatttcccagggacactacacagtctttataattatgatcactacatcttttggataacttaggcttttgcactattttgtcacgatgcctcaaacttttctatcattgtctgtaattactcctataatcttttattataaaatattgaaacaaagtcacatcactaaaaacactgtgagtataatttattagtaagtgtagactgtgtatcattagcaaa 511 228133_s_atggagctgcttcaagaagaaacccggcagaagctcaacgtgtctacgaagctgcgccagctggaggaggagcggaacagcctgcaagaccagctggacgaggagatggaggccaagcagaacctggagcgccacatctccactctcaacatccaggtgcctgccccgtgtccttgcttccttcatgggtcctctcaacttctctgcgctgagatcccccgcaggcagatcgcggtggagtgttggtgcgatggtgcttgaccccccagcttcccctgctattgggtttctccaacgaggagacatggtcttcgcttctcagagtctgtggggccagggacaggggccantcatggtccccctctcaccctaccctggacgctgtccttgtagctctccgactcgaagaagaagctgcaggactttgccagcaccgtggaagctctggaagaggg 512 228195_attgttacctttcagttacatgcctttgatcctaaaattctctacttttgntgccttatcagttctttgcaatctgcctgtggttatcagcacttaaagcacaattttgaaggggaaaaaaatgataatcaccttagtcccaaagaaataatttntgtcaaactgccttattagtattnaaaacagacacactgaatgaagtagcatgatacgcatatatcctactcagtatcattggccttttatcaaatggggaaactatacttttgtattacatagttttagaaatcgaaagttagagactctttataagtaatgtcaaggaacagtaatttaaaaacaaagttctaacaaatatattgtttgcttaatcacaatgccctcaacttgtatttgaataactaaataggacatgtcttccttggagctgtgggcattagttcagaagc 513 228202_atgtttacacctatactgcataatccaacaattttaatttcagttgaagacatgttactaatataactattattaaaagagtagaggatgtgtaattaaccatatcttctaaaacatggttactaaaagaatatgtaacatcaatattgaccttggtttcttacacaagtgttgctaactcaatagtgaaggagacactattaaattttctgaacccatgagagatactagagatggggagtggaaagtgtttggttcagggatatctgaagaacagaagggcagagatttcttaagtgacgcctcatctacaagctggaaattcctaaaaacaagtagaaagcttataaacaacaggtgatacactcacctcactggttttagtaaattaccaatacagaaagtatccctagtcttaaaaacaagtggaaaatttgaactgattagtcatattcctttgattacactgtt 514 228232_s_atcagtcagagtggacaaacctctgtgggaggctctactgcactgagatgcagctcttccgagggggctcctaagccagtgtacaactgggtgcgtcttggaacttttcctacaccttctcctggcagcatggttcnagatgaggtgtctggccagctcattctcaccaacctctccctgacctcctcgggcacctaccgctgtgtggccaccagatgggcagtgcatcctgtg 515 228241_atgcctcctcagacactctcaagaggatggggagatgacatcacttgggtacaaacttatgaagaaggtctcttttatgctcaaaaaagtaagaagccattaatggttattcatcacctggaggattgtcaatactctcaagcactaaagaaagtatttgcccaaaatgaagaaatacaagaaatggctcagaataagttcatcatgctaaaccttatgcatgaaaccactgataagaatttatcacctgatgggcaatatgtgcctagaatcatgtttgtagacccttctttaacagttagagctgacatagctggaagatactctaacagattgtacacatatgagcctcgggatttacccctattgatagaaaacatgaagaaagcattaagacttattcagtcagagctataagagatgatagaaaaaagccttcacttcaaagaagtcaaatttcatgaagaaaacctctggcacattgacaaat 516228469_ataaggttatagccacattcaacttgaatggtcccnaatgttaaatttaccatgaatactgtgtcttacaatgctgagctctcgactagactaaccagaataggaacacagtctcaaaggataccataagacaaacagtatttagacatataaaaaactacagagatgataacttgaagaataaataacgtgaaaaactactatattcttgaatgggagtagaatgtaagctctttgagggcagggactttgactgtcttgttcattgctatatgataatgcctggcccaacagcaggcattctgtagtgtctgttgaacaaacatctaaaatctggcaaagtgaacaatggttcctgaggataagtatttaaataacaaaattaactttcactacaaaagctgccaacttacctttatcttctggtgctatcccctgagctttcttaagatca 517 228504_atgaatgcatgatctcaagccttaactactataatctttttctgcccctcagaaattgaataacctaaccaagatgcctttaggggatgccctaagtaaatgtaatttcagatttcagggnttttttttttttcctctctaagtgttccttccctttcttctcctgctctccatcatgttatggagaccagtgaggaaccagtgttaacttggtgacaatgtgacagctggtgctttatctaagctccgttttctatttcttgggaatgctttattgtggaaactgcttcagatacttaaattgaatcataacttgcttctgtaaattgcgtaaagacaacaaactgattttagtttgaaaagtttatcttttacttgtaaaccttgtttgccagttacct 518228507_atagccccaggtgtatttctgagtgtcaacagtgttaatttcaagcatgctaataaaatgtnnnnncggnnnatannnnnnnnnnaannanncnttnaaantnnnggtttccnntgntaaaancanccncntttgcttttgttagctgtaatattttttgtcatttagataagacctggtttggctctcaataaaagatgaagacagtagctctgtacagggatatatctatattagtcttcatctgatgaatgaagaaattttctcatattatgttcaagaaagtatttacttcctaaaaatagaattcccgattctgtctattttggttgaataccagaacaaatctttccgttgcaatcccagtaaaacgaaagaaaaggaatatcttacagactgttcatattagatgtatgtagactgttaatttgcantttccccatatttcctgcctatcttacccagataactttctttgaaggtaaaagctgtgcaaaaggcatgagactcaggcctactctttgtttaaat519 228640_ataatcttgtgagttgtgacctaggtgaaggtntaatgataacatctggaggaagcatcatttgttcagctacctagggtttactttcagacttttcctacagtttaaagcacttgcgttcagtgtggtacgatctgtttgtaatgttaatcattgactattgttctgctacttggatgttgatagtgaagcagagaacaatttatcatcgtttattatgagtcactatgcacgcaactatgcttaacatggcgaaatgtattaaacactcgtccaactattt 520 228706_s_ataaagggtggcatttgcgtcacgtggaccagggacagtgctgaaatcagcagtgctcagaaacaatttaacatgttgaaacgacaatattctaaaatactgatgaatcttgcatcaatataattattgggttttttttctttttcctgctgtataactccttgccatgcaaactctcaagaggccaatatattcctggccatgtttgaatgagcctcttaaaataaacttagagccatgcaaatgccagcagcttaatggatttcatggaatgaaataccgtgattaactcatagctacatatcattgcataaatgggatttatcttttttctcacttatttttgcggtgaaa 521 228707_atagagccatgcaaatgccagcagcttaatggatttcatggaatgaaataccgtgattaactcatagctacatatcattgcataaatgggatttatcttttttctcacttatttttgcggtgaaagtcgagggcatgcaagagtttctcttccagaagccaagaggagaacaaaggtcctaatgctgtactattccaccctttggacgcctcatccaggacgcagaggactctaggtttaacatttt 522 228750_atgacccagagtcacctaagagaactcttccaacttaaatgactagggtgtgtaatcagttgcttcttattctgtgtctcagatttcctagtccatgacatttaatagtgagtatagagtaggatattctatacattttagtatttggcccttggaaacaaagttaaataccatgtcactcagaagactctcaaagtttgtgtataaatggcgaagtatgcactatgagagattctaatccattcacatcattcttgagttgtgcaaatacacttggctttgatttcacttggtgatctaaatttgtttatttaagctgcaagaaagttacattaatttggaatgtgtcatcacttggacccagtatatcagatttttattgagtaaaatgttaaaaataataagtgtaactcagattctggatgttcgagtttacaatacattgcctgtaataaaagctgattctgaagtgcatttttcttgacttactttggcag 523 228766_atatgcacgtacaaatttcttaacctgttatcaatgtctgagctacataattatctttctagttggagtttgttttaggtgtgtaccaactgacatttcagtttttctgtttgaagtccaatgtattagtgactctgtggctgctctcttcacctgccccttgtggcctgtctacaattctaaatggattttgaactcaatgtcgtcgcttctggtttcctgcatataccaatagcattacctatgactttttttttcctgagctattttcactgagctgagctaatgaactaaaactgagttatgtttaatatttgtatcaaatacataaaaggaatactgctttttccttttgtggctcaaaggtagctgcatt 524 228846_atggaatcttttccaataaccagctaaagatttgcactgaaatacaacttgtatgccttttgcatttttaaagcctgcttcctggatttaagcagagtgatagtgttcaaagagccagttcagcctgtaacatatttgaaaaagatatgtctgcactttgaggtcccttttgaatgccattcactagacctctcaagcattttgtttcattgctacatccaagcgcctcacaagtccacaatgcgggacagcatcaaaagctcaagactttgnaaaaagcttgtgggcttgcactgggggagggaagggaacaaaatttgtgtacttctttgtttaatttagaaataaggcatccaagagatgccattattttctgtgtttcaattgttgtgcctttgagttaaactgcatttttgtcttttggttgaaatctgaaatgtactgtcccaatat 525 228854_atctccttatctgttctagttccgaagcagtttcactcgaagttgtgcagtcctggttgcagctttccgcatctgccttcgtttcgtgtagattgacgcgtttctttgtaatttcagtgtttctgacaagatttaaaaaaaaaaaaaaggaaaaaaaaagaaaaaatgaatttactgctgcaggtttttttctctctccatgtgtcactaagtgaagtttgtgccttctatagcaaagagaatattttttacatcctactaacagtagatttttttgtagtgaacattttttgtatttttatttataagtctcataagaaaaatagcaatgttcagttgtataccttgaatctgcagttaga 526 228885_ataataggtcttgcaggtttccttttgaattttaagtatcataaatattttttaagtaaataatacggggtgtcagtaatatctgcagaatgaatgcagtctttcatgctaatgagttagtctggaaaaataaagtcttattttctatgttttattcatagaaatggagtattaatttttaatattttcaccatatgtgataacaaaggatctttcatgaatgtccaagggtaagtcagtattaattaatgctgtattacaaggcaatgctaccttctttattccccctttgaactacctttgaagtcactatgagcacatggatagaaatttaacttttttttgtaaagcaagcttaaaatgtttatgtatacatacccagcaacttttataaatgtgttaaacaattttactgatttttataataaatattttggtaagattttgaataatatgaattcaggcagatatactaaactgcttttatttacttgtttagaaaattgtatatatatgtttgtgtatcctaacagctgctatgaa527 228961_atgagaacatcagatctaatagagcatagtgatactatttaatttaaccaaagtctctagtgaatatttcanctttgaatgtaaactaacaaataaacctgaccaccaaggagattgtttgcccagagtttcaaagcacattgtctacaaatggaaattgaaataatttataaaatattgacgttactatgttttttaaaaagttcctaattttttcactaaatggaggaaactattagttttattgttaaatatggtagatattaatattcctcttagatgaccagtgattccaattgtcccagtttgaaataagtaccctgtgagtatgagataaattagtgacaatcagaacaagtttcagtatcagatgttcaagaggaagttgctattgcattgattttaatatttgtacataaacactgatttttttgagcattattttgtatttgttgtactttaatacctggtgtacagttccagaaa 528 229070_atgaaggatgctgaggacctagatgagaagttacctgcaaaaggcaaaagggttacttagtgtcagaaccaaggcaatgacttctctctcccagatctcctagctactggtcctgggccanntttttttttttaaataatcccaacntttctttaaaagacaagcatttcagtaagctagttattttcatgggttgctcatccatttttttcagtgatctaaaaatgtagggagatggctactactgaagttgtctgtctacttgggataatagcaaattaattgaagacaatgggaaagtaagttataaaaaatactgggaaatctgtttctcttctgagcaagcattcagggcaggtataaacatcaaacatagtgacattgtcaaaacctcttccatt529 229254_atggaaagagaaacgtggctcaagtgctggctcaccttctagctgtgtggccctgggcaggttactgaggctcttccaanctcacttttcacatgtaaaatggcatttctaaaagtacctaccctacctcaaaggaattctgaaaaaagtaagtgaatttgtnannnaagcaaagcactcacaatatgcctgacacacaaactgcttaataaatgttagtaatttttaaaacctcctcataagcggcttagaaattattcatgtttggtacatatttattgcaagtcaagcagatccaacttttttgaaagctggtggtctaggagtatagttttaattatatttgtaaatactcaaaagtattagatgccagtctaatttaaatgcagtctgactgtagcgagtaactgacctgggcaatg530 229530_atgggactcagttcttagagaagtcttttggtcttagagttcatcaagcagagaaggggaaggacatggtccaggaaaataaatcagcacacaaagagatggggtcttgagggtgcatagtacattctggacagccagttacctgggatgagttgggagggaggagaataaggacaaaagaccatctgggcaaaaatcacgaaggggtatgtgtgtcatgtaaaggtgtgccatgatagttattcatattgctattgtaatattaatatatagtaattaactacacatgacacagctttacatgaccttaagtagttatcaacattaccataatagtaatattaataactacaataagagccattattattcacttgagg 531229659_s_atgttagcaagtgccagcttgtaggctggttgaagtacagaactcagaggaaaaaagaaattaaattttagctttctggagagcagcccctctctggcaccatcaaacacttctttgtttcccttcaacttggaactcttcaaacatcaggggttgtgagggtttggccattcttttatcttgggtccatgtgagtgacagaaatggtgcggcctgggaaagatctccctcctttacattttctcttctccctcctcctccttattctaaaactgtgcctccaacagaggggcaggggctcttgtagagagagatccctggcccaggacaggagatgccaaatctaatttatctcactgagggc 532 229831_attttcctaccaatttcacattttgcagaaacttgttcacatttccaacaatatcagaattagaaaacagttcagataacaagaaagattaaaaattagggaaattctgatatcaccataaagcactattttacatttagagattacatttaagataaagtcatcatacacaaaaacaataaatatttataactttctctataaggtccgcatatactgtatatattgaaacaatctgaatgactagtagatttcatatgaccattgttatttccactttctccaatacttgtattttatgctacatgtaatgaagttggacctttttattatttagtaattcctatatgttcctatacttttcattttcaanatgattgctctattgtttcatgttgtttctagcaatatatctccatgagatatgcactttgtttcatattgaaaagtataaaatttatctttcaattcctgtgtgtgtatcctatggttatctgtatgtat 533 229839_attcccaacccggttctggcaaagaatccagttatcccttccatgaagacgcacataactctcttacttggtctttccattagggacaacataagtcttgttttacatcaaataaaaacaatgttaaaaagtgtgtgaaccttaaaaatggaagtctactagtttacatacctacttcagaggacatggaaatgaccatgggcctgcatttcagggaccaaagcaaattaggcctggcctaaaatacatcagaccttttg 534 230087_atgttgaccccaactttggaactcagatcataggatctcccagaggtttcaggtgttcctaagaagcttctaaaggaagttttggaagaaagactaataggtgtaaacatataaacatatatattatatatagctatatatatttaaagagatctctacatatatatatatataaatacaactactgtactctctgcatctgtacaaagtatgagttaaactgcccaggtagtgtgagatacgtaatgcatgaatgtgaatatcctgaaatctgccttcttagcaacgtgccgcgtgtactggagagaggacagttgctcctgggagttctctcaatgggcaaatgtacaagttgatgccgtcttatccaccaacaagccattaaggttggtttcctgctgagacttttgtaccggaagcgagaccggcagcactgggggtgtccatatgccacttatgagg 535 230264_s_atggccaaggcacatttgactcctgagatgaattttttgtggtcataatcaaatacttagttgtttttgatgccccaaaataaagtgagaatggtaatttgccaggaattcttcataacagtatcttacaaaaaacgtgttgctctcttcacagtattatgtgtaaagtcattgtttaaagcacgaatgttccctctggggtacttgttaaagctaaatttattttgcttccctccacttagaagtgctgcacactttacagcagcttcctttctttccatngcactgcctagttaacagaagtcttataaaaatttaaaaagacacatttcttacaaaaaagagttgaatgaggtaaaatggcattagatggctctatattttttaaagctatgtaattgttcagcgtcacttttctaagtacttatacatatctaaacatgtcttcatggtttatattttcacttatatatgctgggctggattaagctttgt 536 230595_atggggcagagggactatgttgtgagcctngcnaaagaagnttgtgtggggactgtgggcagtgaatgcgttgggaacaatatggaaaactgggagctgccttggaatctacagggccgnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnggctgaagaaaagaagaatggtattcatgcagttcccattttacagatgaaaacaagaggactttttctgtgaagtcaagaaagtggttacaatggtactttcagcctgtccgaattatgtattgcccctcccctttttattaataacattgaagtgtgatgggacaaccactgaagccgtctgttgaaacctgctgggactttttagccattctcttcaacataaagaatgggtgtttttggagggggtgagaggaatggggaaatgttgtcaaagagtacaatgttttagttgagacaggaggaatatattttgttgagatctacagcacagcat 537230788_atgatagcgaatgcactcagggtcagcagtggagtttaaaaattgtctcttttcaacttatttaaatgacagcacctgagaagaggaaccgttttacactggatgtttctcatgtagaacaagaaatctttctggaattgatgtttacatgtctgttgttggtcatctctcctgtgtcttaaatactttaatgttggaagagcatagtgtttgggctagtgggtttctgacagcccatgggaatgccctgaaactactgtatctgatgtttgttttcgatgaggttccatgttttgttttc538 230830_atgcagctgtggtggtcattataagcatngtccntcctgggaagaagcatccaggcaagcagaaaagaaaagatgcagccaccagaaaaagaaactccagaagtcctgcatttggatgaggccaaggatcacaacagcctaaacaacctaagagaaactttgctctcagaaaagccaaacttggcccaggtggaacttgagttaaaagagagagatgtgctgtcagttttccttccggatgtaccagaaactgagagctagtgagggttcagagaagccccatcctaagccagacacatgatgtgggctcagctcagtggcctgaaacctctcaggttttagagtctctcccaagaagccgcttttttc 539231120_x_attactagttgttttacactctcttttcttattcttagggcttttgtgtatgtctnactnntntttnaannanntncncnnnnanncagaccttaanttttatatttttttaaagtngctaacatagcngnaggcacttaagcatttagtcaatgatattggtagaaatagtaaaatacatcctttaaatatatatctaagcatatattttaaaaggagcnaaaataaaaccaaagtgttagtaaattttgatttattagatattttagaaaaataatagaattctgaagttttaaaaatgtcagtaattaatttattttcattttcagaaatatatgcatgcagttatgttttatttgattgttgacttaggctatgtctgtatacagtaaccaa 540 231579_s_atgagtaggttcggtctgaaaggtgtgggcctttatatttgatccacacacgttggtcttttaaccgtgctgancagaaaacaaaacnggttaanaananccgggtggnnagntgacagaggnaanccgctnaaataccttcacaataaatagtggcaatatatatatagtttaagaaggctccccatttggcatcgtttaatttaaatgttatgttataagcacagctctcttctccaattttcatcctgcaagcaactcaaaannnttnaaannaannttnnnntgtagttattttcaaatctttgcttgataagtattaagaaatantggacttgctgccgtaatttaaagctctgttgantttgtttccgnttgganttttgggggaggggagcactgtgtttatgctggaatatgaagtctgagaccttccggtgctgggaacacacaa 541 231773_atggaacctataaatgtagtttcatctgtcgtcaattactgcagaaaattatgtgtatccacaacctagttattttaaaaattatgttgactaaatacaaagtttgttttctaaaatgtaaatatttgccacaatgtaaagcaaatcttagctatattttaaatcataaataacatgttcaagatacttaacaatttatttaaaatctaagattgctctaacgtctagtgaaaaaaatatttttaaaatttcagccaaataatgcattttatttataaaaatacagacagaaaattagggagaaacctctagttttgccaatagaaaatgcttcttccattgaataaaagttatttcaaattgaannngtncctttcacangtnnatgattaaatctganttcttaatnatatatcctatgctgattttcccaaaacatgacccatagtattaaataca 542 231925_attctttttgagtgatagtgccattgaatgagcagtatggaaacagtgttacttgatattttgagctttctcaggtttatctaaatcagtggtagcttaacaaaacccagactaattgtgtgtaattgtatttttaataaaaggaaagtacatttcctataatagcatagtactgtttgcatgtaagagtatgcaaaaccttgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtcttagtgtgtgtaaggcatggcagccaactttgtatctgctatttttagtacgagcagagcttcataattgtggtcactagaactgtacttaccatggacagttaaaact 543 231975_s_attctctcagtttaaacatcttaacagagaatttgttactgtttattaaaagaattgcatttggaagcaagaaaacaaccggatttgcaatcatgtgaagaaacaataatgcctttattatcaagtgttaagcacaattcttataacaaactgtgataaattctttttgtttttttttcctttgccccattattttcttatgaacaaaccaaaaattcatggtgagcagttgcagtgttggctgatatatcttttatgtacagggaatttgaaaaggacagtggattcatttagaagtgtaactggtgctgtgattatagcaatacatttgttagttgtacttcatctttttcatgctagctttttaaatgtttagttttcctcttgtcatggtcagctgctgaatttacttgaag544 233565_s_atagattctggccacggctgggaacgttgtcaccctgaccatcatccccagtgtgatctacgagcacatggtcaaaaagttgcctccagtcctgctccaccacaccatggaccactccatcccagatgcctgaagccactgcagggcagggcaggcagggggggcttcccgccctcctgcagcaaagggcaaccaccctcggatgatgggttgcagccggcctgctgcttaaggtgggggctgccatgaggggggcgtgtccaggagggtgaccatgggatggcttatacacacaggcctccttggagcctcagactccaagctaggctgaggctcaggcagggcccacaggcagccgattctcttgtgctgatttaaatgctggacacggaggcaggctgtttaaacgctgcttaaagtcgcaactgggcccctttcaagaaattttgctctaccaggaaaacagttacacattttaagagaacagagctacgttctttgtgagagctttttccttgccttgacttgctctttgtcacagactgca 545 234764_x_atgtcaccatctcttgttctggaagcagctccaacatcggaagtaattatgtatactggtaccagcagctcccaggaacggcccccaaactcctcatctataggaataatcagcggccctcaggggtccctgaccgattctctggctccaagtctggcacctcagcctccctggccatcagtgggctccggtccgaggatgaggctgattattactgtgcagcatgggatgacagattgagtggttttat 546 234987_atgtttactctgagattctgtagtcctaatattgtatcattgtgctgtctgcaaaacaacttgaatctattttgnttgcatcttttgttacatgtaacgcagctgtactttatgttctttgcaactgtttccattatgagaacgctgtgctatttacaaggttacatttttcttggccaggcgaggtggtcatgcctgtaatcccagcactttgggaggccaaggtgggcggatcacttgaggtaaagagttgagaccagcctggctagcatggcgaaacccagtctctactaaaaatancaaaaattagccgggtgaaattagccgggcg547 235146_atggtgttttaaggttagcacatgcacaaaggaacgagttggtttaaaaagataaatcactgcaaagaatgaaattggcttattcacatcaaaactagataagatgctaaaaaaaaaagatatgaaacagaactaacctatagtttcctgaaatcagtacagtttaatttataagaagctagaaagtaatgcaccttgattgttttaggaatgatttatgtgttgcaattttaatttatttaaagcatgtctactgtgtttgtcctaagagaaatatttcaacaaaacgtgctctgtgtttaagatatgtttaggcagtagttagcaactctgaaagtagaaactggaaatgtttattgtgaggcttgttgcagaatttccattttgtgagttactacttagtttcatgtcagcctaaaattgtaaattccctgtagatcttcaccccattgtggtgtcatcaatgaatccaaagcaggtgccattattt 548 235766_x_atgcagggtcataatcacacagcagtgccttatatagttgccataagacttcagtgcagtacaacatanttttacngctacatatcagggcatattctatatggtgtatttgtgttagaataacacattaaatgtctttaaacataaaaataagaatgtttgcatgtttcagttttcaagaaccaaatgagtaattagctatagattccactggccttaaacatacaattaagtgtatacatgatatagtgcacacacaaaagccacctttaattattgaaataacctgtattctttttggaaatcatttaagtttggtattgaagtactatattttttgtgcatcaatgtatttttctatttacaagcctatgt 549 235849_atggagatcgtgttctgctttttacatgaggagcagaactgggccatacacgtgttcaagaactaggggagctacctggtagcaagtgagtgcagacccacctcaccttgggggaatctcaaactcataggcctcagatacacgatcacctgtcatatcaggtgagcactggcctgcttggggagagacctgggcccctccaggtgtaggaacagcaacactcctggctgacaactaagccaatatggccctaggtcattcttgcttccaatatgcttgccactccttaaatgtcctaatgatgagaaactctctttctgaccaattgctatgtttacataacacgcatgtactcatgcatcccttgccagagcccatatatgtatgcatatataaacatagcactttttactacatagctcagcacattgcaaggtttgcatttaagttaaaaaaaaaaagaaaaaaaacctaagggtgaaacgatgccactttgacgc550 236300_attgactttcatacacacccagtacatctcaaaggatgctaagggacattttctgccagtagagttctccccctttttnggtgacagcaatattattatgttcacatctaactccagagcttacttcctgtggtgccaatgtatttgttgcaatttactacatttttatatgagcctatttataggtgccattaaactcaggtctttcaaatgaaagagtttctagcccncttagggaaaaagataattgtttagaaaaccataaaatcaatggtaggaaaagttggaactggttacctggatgccatggttctctgttaaataaagtaagagaccaggtgnannnnnaannnnnannanngntattttcagcatgctaataaatgtctttccggttatatatctatctaaaattaacctttaaaatattggtttccttgataaaagcaccactttggcttttgttagctgtaatattttgtcatttagattaagacctggttaggctctcaataaaagatgaagacagtagctctgtacagcggataatatc551 236313_atgctagttgcattatactgggtcatgaaaaattatcccttgaaatagatatgaaacatgttacttcatttctggtttaaataacttgtggaatctttcctaatgacaacntgatattaagggaaactaaagaaaatgttattgtggatcccacagtactatattacactgtttttttttgtttgttttgttagtttttttttatttaaagcaaacctcaaacctcaaacattattgggtatcaattaccacctggttgtattaaaatagtaacttatcaatgccatgtaaaaattaattccattttcgaagccacctggcagacaggtttagctgtttcatcagcagcctaatatatactgttaaatttgttaaggatttcactttgaaggatacatgcaaaacatatagttactattttcatgagtcctgcttctagctccattgtggaatacagaaaattaaatatacctgttaagttcgtatctaaacctaagacattaccaaggtttgtacaaattctactacctgacatttattccaaga552 238143_atctcccctgaagaacgtgtccagcaacgcagagtgccctgcttgttatgaatctaatggaacttcctgtngtgggaagccctggaaatgctatgaagaagaacagtgtgtctttctagttgcagaacttaanaatgacattgagtctaagagtctcgtgctgaaaggctgttccaacgtcagtaacgccacctgtcagttcctgtctggtgaaaacaagactcttggaggagtcatctttcgaaagtttgagtgtgcaaatgtaaacagcttaacccccacgtntgcaccaaccacttcccacaacgtgggctccaaagcttccctctacctcttggcccttgccagcctccttcttcggggactgctgccctgaggtcctggggctgcactttgcccagcaccccatttctncttctctgaggtccagagcaccccctgcggtgctgacaccctctttccctgctctgccccgtttaactgcccagtaagtgggagtcacaggtctccaggcaatgccgacagctgccttgt553 238750_attttgtccatagaggcttcaagatagataggtaagagnccagtagtgttcataagaagccaatagagagcaggagccactttatcaggtggcaggtgtcctgggcctccctgctggctagtcccaagcggtggtgttgccaggatgtcttggaggtgataatgggacacacagaggcactgagtctccataggttaaaatgccaccaaaactggcctttgcctaatatccctcattgactatttagcatttaatttatttattttcctgacatttctgcaagctttgtatttatatttccactttatagatgaggaaatttgaggctcttagaggtaaaatgacttgcccaggtcacacaggaagtggcagagacaagctttttaaataagaaaaaattaataaaatataatatgagagtaacttaaaatattaataaaccacaattttaaattaattaaccgtgataaccaacattaataaaagttaagataccaaaacactggtgtctaattctttcaac554 238751_atgttctgttgtttatccatgaagcctatatatttctagtgcaaaangcccagtgggtctcaaaacattcttggaggggtttgacacactgctattagtagtgactcataattccacgattccctgggatacagagaaggcaggggggtagtactgtttgaacaaaaatcttcccaagaccctggcaaagagatcttccttaggaatcagtggcatatgcgtttatgttctttaacagggaaagtaaaagtgagcgcacttttttgaagctcataaatactcatgtgactgtaaatttagaaatgttaattaattgggcctaatgtttgatctggaaaagtacttagcagtcaccaggaatttgccttgaactgactcgaaccacaaatcagaaccgtatttccacaattta555 239272_atgcactgttaaaatccggctaggccaagatttcccaatgtcttgaagccaatggctaggaaaacagctgagcctgggactggactttgtcagtaacctctcttccctagggcacgggaggagtngggtgaataggacctcttggcttgaggaccatgattgtgaatacagacatttaattcagaatgacacctacattgatgaattttcattgtacaagtgtttttccagatcaaacacaaaacccatgtaattccttgataaattttcaatgcagggcagataaactgttgctaac556 241994_atgtgatcttggactgtcaattcccctncctgtgatccattttactgcaaacataagggttgcagtaaagggttgtctcacgtcttctgctttaaaagcctataaatatatgacctgaaaactccagttacataaaggatctgcagctatctaaggcttggttttcttactgtcatatgatacctgggtctaatgaactctgctgagatcacctcaagtttctgcggttggtaaagagaacaagggaagaacaaacatcccttttattgctccaaatggtgatttaatccctacatggtgctgggtggacaatgtgtcactgtcacatgccttnactgtataaatccaaccttctgccagagagaatctgtggttctggccatggagggaggatagtggaaatgatatagttggactggtgcttgatgtcacta557 242317_atatgtgattatacttctctttgacttgtcagcttagctttagnngatacactctggtgcccaactattattgtatcagtgaacttnccactttncttttnctctcaatttttgttgtatcattcctaccttgtgaggacatataatatttacattctgttgtcatcctcacatttcttagttccacagtttaaatgtatttgaaactcaaaacattcccattaatctcttggtcagctgaaattaatgatttaatagtttccttaaaaaagactcatggaacaatttccctaaatttttgccatgtcaaatatgtttatctgtagcctttacacagtaaaaacaatttggctagataatacaattctcagttcatat 558 242447_atagggcacttctcaacattaattttggaattattcaccatttaaaaattgtcactgctctttttcattactgtagataactgagagttagctgttctaggaaaaggccatgtttcagttagtgctatgacttcttttttcgattaaggttgaagcagtgttctcttagtagcctgaacacttctcaaagcgacttatcactagcggctttaatattgagcttctatatcgttgtgtccacctcactttttaaggctgttcatacctggcaatattcacttactctgctatttttaaaaactattttaaagttttaagcacaatgttgactcttctgtaatttcctaaaattatattgttttcctacagacagctcaactttccttgatatgt 559 242601_atctcattattcctttacatgcagaatagaggcatttatgcaaattgaactgcagtttttcagcatatacacaatgtcttgtgcaacagaaaaacatgttggggaaatattcctcagtggagagtcgttctcatgctgacggggagaacgaaagtgacaggggtttcctcataagttttgtatgaaatatctctacaaacctcaattagttctactctacactttcactatcatcaacactgagactatcctgtctcacctacaaatgtggaaactttacattgttcgatttttcagcagact560 243278_atataaatgaccagactttttctaagaaaaatgttgctttaatgcatttcatgaatttttactcttatatcattgcttgctagtaatagcaaatctgcttttctgcatctgctttgcgtagctattgtaaggctttgaactaatgtatgtatttattgcttgaacttctgtgcataccttataaagcataatgtctgacaatttaaatggctcatgtattcttgcttntatcataagctgattatggggactatgatcttttgtatacagcaaattttaaactgtagcacaaacatctgtttatgtattggtggaatatacctgttttatttatcttttttgaggtaaactaatttttgatacttttcattactgtgtactatgttcatactttgaattctctgacgttagaagtcatggttgagaattgtaacagctgttattcgttctgtattcatggctttc561 200832_s_ataaaagcgaggtggccatgttatgctggtggttgccagggcctccaaccactgtgccactgacttgctgtgtgaccctgggcaagtcacttaactataaggtgcctcagttttccttctgttaaaatggggataataatactgacctacctcaaagggcagttttgaggcatgactaatgctttttagaaagcattttgggatccttcagcacaggaattctcaagacctgagtattttttataataggaatgtccaccatgaacttgatacgtccgtgtgtcccagatgctgtcattagtctatatggttctccaagaaactgaatgaatccattggagaagcggtggataactagccagacaaaatttgagaatacataaacaacgcattgccacggaaacatacagaggatgccttttctgtgattgggtgggattttttccctttttatgtgggatatagtagttacttgtgacaagaataattttggaataatttctattaatatcaactctgaagctaattgtactaatctgagat562 201147_s_atgagtcggagatgatgcagcacacacacaattccccagcccagtgatgcttgtgttgaccagatgttcctgagtctggagcaagcacccaggccagaataacagagctttcttagttggtgaagacttaaacatctgcctgaggtcaggaggcaatttgcctgccttgtacaaaagctcaggtgaaagactgagatgaatgtctttcctctccctgcctcccaccagacttcctcctggaaaacgctttggtagatttggccaggagctttcttttatgtaaattggataaatacacacaccatacactatccacagatatagccaagtagatttgggtagaggatactatttccagaatagtgtttagctcacctagggggatatgtttgtatacacatttgcatatacccacatgggg563 201162_atggaatgtcactggtgcccaggtgtacttgagctgtgaggtcatcggaatcccgacacctgtcctcatctggaacaaggtaaaaaggggtcactatggagttcaaaggacagaactcctgcctggtgaccgggacaacctggccattcagacccggggtggcccagaaaagcatgaagtaactggctgggtgctggtatctcctctaagtaaggaagatgctggagaatatgagtgccatgcatccaattcccaaggacaggcttcagcatcagcaaaaattacagtggttgatgccttacatg564 201163_s_ataggtgaaggtgccgagctataaacctccagaatattattagtctgcatggttaaaagtagtcatggataactacattacctgttcttgcctaataagtttcttttaatccaatccactaacactttagttatattcactggttttacacagagaaatacaaaataaagatcacacatcaagactatctacaa565 201185_atctcaaagactctcccgtggatgacggatgaggactctgggctgctggaataggacactcaagacttttgactgccattttgtttgttcagtggagactccctggccaacagaatccttcttgatagtttgcaggcaaaacaaatgtaatgttgcagatccgcaggcagaagctctgcccttctgtatcctatgtatgcagtgtgctttttcttgccagcttgggccattcttgcttagacagtcagcatttgtctcctcctttaactgagtcatcatcttagtccaactaatgcagtcgatacaatgcgtagatagaagaagccccacgggagccaggatgggactggtcgtgtttgtgcttttctccaagtcagcacccaaaggtcaatgcacagagaccccgggtgggtgagcgctggcttctcaaacggccgaagttgcctctttt 566 201261_x_attctctctttctgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtcttgtgcttcctcagacctttctcgcttctgagcttggtggcctgttccctccatctctccgaacctggcttcgcctgtccctttcactccacaccctctggccttctgccttgagctgggactgctttctgtctgtccggcctgcacccagcccctgcccacaaaaccccagggacagcggtctccccagcctgccctgctcaggccttgcccccaaacctgtactgtcccggaggaggttgggaggtggaggcccagcatcccgcgcagatgacaccatcaaccgccagagtcccagacaccggttttcctagaagcccctcacccccactggcccactggtggctaggtctccccttatccttctggtccagcgcaaggaggggctgcttctgaggtcggtggctgtctttccattaaagaaacacc 567 201792_atccaccgctggctgggaggagtcggagactgagacctacacagaggtggtgacagagtttgggaccgaggtggagcccgagtttgggaccaaggtggagcccgagtttgagacccagttggagcctgagttcgagacccagctggaacccgagtttgaggaagaggaggaggaggagaaagaggaggagatagccactggccaggcattccccttcacaacagtagagacctacacagtgaactttggggacttctgagatcagcgtcctaccaagaccccagcccaactcaagctacagcagcagcacttcccaagcctgctgaccacagtcacatcacccatcagcacatggaaggcccctggtatggacactgaaaggaagggctggtcctgcccctttgagggggtgcaaacatgactgggacctaagagccagaggctgtgtagaggctcctgctccacctgccagtctcgtaagagatggggttgctgcagtgttggagtaggggcagagggagggagccaaggtcactcca 568 202237_atctactacatgattggtgagcagaagttctccagcctccccctgggccgggaggcagtagaggctgctgtgaaagaggctggctacacaatcgaatggtttgaggtgatctcgcaaagttattcttccaccatggccaacaacgaaggacttttctccctggtggcgaggaagctgagcag569 202238_s_attcgtcactgactactcagaccagaacctgcaggagctggagaagtggctgaagaaagagccagaggcctttgactggtccccagtggtgacctatgtgtgtgatcttgaagggaacagagtcaagggtccagagaaggaggagaagttgagacaggcggtcaagcaggtgctgaagtgtgatgtgactcagagccagccactgggggccgtccccttacccccggctgactgcgtgctcagcacactgtgtctggatgccgcctgcccagacctccccacctactgcagggcgctcaggaacctcggcagcctactgaagccagggggcttcctggtgatcatggatgcgctcaagagcagctactac 570202310_s_attggcctacatggaccagcagactggcaacctcaagaaggccctgctcctccagggctccaacgagatcgagatccgcgccgagggcaacagccgcttcacctacagcgtcactgtcgatggctgcacgagtcacaccggagcctggggcaagacagtgattgaatacaaaaccaccaagacctcccgcctgcccatcatcgatgtggcccccttggacgttggtgccccagaccaggaattcggcttcgacgttggccctgtctgcttcctgtaaactccctccatcccaacctggctccctcccacccaaccaactttccccccaacccggaaacagacaagcaacccaaactgaaccccctcaaaagccaaaaaatgggagacaatttcacatggactttggaaaatatttttttcctttgcattcatctctcaaacttagtttttatctttgaccaaccgaacatgacca 571202311_s_atgctccccatttttataccaaaggtgctacatctatgtgatgggtggggtggggagggaatcactggtgctatagaaattgagatgcccccccaggccagcaaatgttcctttttgttcaaagtctatttttattccttgatattttttntttntttttttttttttttgtggatggggacttgtgaatttttctaaaggtgctatttaacatgggaggagagcgtgtgcggctccagcccagcccgctgctcactttccaccctctctccacctgcctctggcttctcaggcctctgctctccgacctctctcctctgaaaccctcctccacagctgcagcccatcctcccggctccctcctagtctgtcctgcgtcctctgtccccgggtttcagagacaacttcccaaagcacaaagcagtttttncccctaggggtgggaggaagcaaaagactctgtacctattttgt 572 202404_s_atactttcccatgagtgtgatccacattgttaggtgctgacctagacagagatgaactgaggtccttgttttgttttgttcataatacaaaggtgctaattaatagtatttcagatacttgaagaatgttgatggtgctagaagaatttgagaagaaatactcctgtattgagttgtatcgtgtggtgtattttttaaaaaatttgatttagcattcatattttccatcttattcccaattaaaagtatgcagattatttgcccaaagttgtcctcttcttcagattcagcatttgttctttgccagtctcattttcatcttcttccatggttccacagaagctttgtttcttgggca 573 202450_s_atgaacaacgcctgtggcattgccaacctggccagcttccccaagatgtgactccagccagccaaatccatcctgctcttccatttcttccacgatggtgcagtgtaacgatgcactttggaagggagttggtgtgctatttttgaagcagatgtggtgatactgagattgtctgttcagtttccccatttgtttgtgcttcaaatgatccttcctactttgcttctctccacccatgacctttttcactgtggccatcaggactttccctgacagctgtgtactcttaggctaagagatgtgactacagcctgcccctgactgtgttgtcccagggctgatgctgtacaggtacaggctggagattttcacataggttagattctcattcacgggactagttagctttaagcaccctagaggactagggtaatctgacttctcacttcctaagttcccttctatatcctcaaggtagaaatgtctatgttttctactccaattc 574202859_x_atgtacccagttaaattttcatttcagataaacaacaaataattttttagtataagtacattattgtttatctgaaagttttaattgaactaacaatcctagtttgatactcccagtcttgtcattgccagctgtgttggtagtgctgtgttgaattacggaataatgagttagaactattaaaacagccaaaactccacagtcaatattagtaatttcttgctggttgaaacttgtttattatgtacaaatagattcttataatattatttaaatgactgcatttttaaatacaaggctttatatttttaactttaagatgtttttatgtgctctccaaattttttttactgtttctgattgtat 575 202878_s_atatccgaattctccatatattcactaatcaaagacactattttcatactagattcctgagacaaatactcactgaagggcttgtttaaaaataaattgtgttttggtctgttcttgtagataatgcccttctattttaggtagaagctctggaatccctttattgtgctgttgctcttatctgcaaggtggcaagcagttcttttcagcagattttgcccactattcctctgagctgaagttctttgcatagatttggcttaagcttgaattagatccctgcaaaggcttgctctgtgatgtcagatgtaattgtaaatgtcagtaatcacttcatgaatgctaaatgagaatgtaagtatttttaaatgtgtgtatttcaaatttgtttgactaattctggaattacaagatttctatgcaggatttaccttcatcctgtgcatgtttcccaaactgtgaggagggaaggctcagagatcgagcttctcctctgagttctaacaaaatggtgctttgagggtcagcctttaggaaggtgcagctttgttgtcctttg576 202917_s_atggcatcatgttgaccgagctggagaaagccttgaactctatcatcgacgtctaccacaagtactccctgataaaggggaatttccatgccgtctacagggatgacctgaagaaattgctagagaccgagtgtcctcagtatatcaggaaaaagggtgcagacgtctgg 577202998_s_atgccagtcttgaccgggatgaggcccacagacaggttgtcatcagcttgtcccattcaagccaccgagctcaccacagacacagtggagccgcgctcttctccagtgacacgtggacaaatgcgggctcatcagcccccccagagagggtcaggccgaaccccatttctcctcctcttaggtcattttcagcaaacttgaatatctagacctctcttccaatgaaaccctccagtctattatagtcacatagataatggtgccacgtgttttctgatttggtgagctcagacttggtgcttccctctccacaacccccaccccttgtttttcaagatactattattatattttcacagacttttgaagcacaaatttattggcatttaatattggacatctgggcccttggaagtacaaatctaaggaaaaaccaacccactgtgtaagtgactcatcttcctgttgttccaattctgtgggtttttgattcaacggtgctataaccagggtcctgggtgacagggcgctcactgagcaccatgtgtcatcacagaca 578 203083_atcaggaaatagtcactcatcccactccacataaggggtttagtaagagaagtctgtctgtctgatgatggatagggggcaaatctttttcccctttctgttaatagtcatcacatttctatgccaaacaggaacgatccataactttagtcttaatgtacacattgcattttgataaaattaattttgttgtttcctttgaggttgatcgttgtgttgttttgctgcactttttacttttttgcgtgtggagctgtattcccgagacaacgaagcgttgggatacttcattaaatgtagcgactgtcaacagcgtgcaggttttctgtttctgtgttgtggggtcaaccgtacaatggtgtgggaatgacgatgatgtgaatatttagaatgtaccatattttttgtaaattatttatgtttttctaaacaaatttatcgtataggttgatgaaacgtcatgtgttttgccaaagactgtaaatatttatttatgtgttcacatggtcaaaatttcaccactgaaaccctgcacttagctagaacct579 203325_s_atcccacctggagctgaatcacatgacctagctgcaccccagcgcctgggcccgccccacgctctgtccacacccangcgccccgggagcggggccatgcctccagccccccagctcgcccgacccatcctgttcgtgaataggtctcaggggttgggggagggactgccagatttggacactatatttttttctaaattcaacttgaagatgtgtatttcccctgaccttcaaaaaatgttccaaggtaagcctcgtaaaggtcatcccaccatcaccaaagcctccgtttttaacaacctccaacacgatccatttagaggccaaatgtcattctgcaggtgccttcccgatggattaaag 580 203570_atctggaggacagcacctgtgacttcggcaacctcaagcgctatgcatgcacctctcatacccagggcctgagcccaggctgctatgacacctacaatgcggacatcgactgccagtggatcgacataaccgacgtgcagcctgggaactacatcctcaaggtgcacgtgaacccaaagtatattgttttggagtctgacttcaccaacaacgtggtgagatgcaacattcactacacaggtcgctacgtttctgcaacaaactgcaaaattgtccaatcctgatctccgggagggacagatggccaatctctccccttccaaagcaggccctgctccccgggcagcctcccgccgaggggcccagcccccaacccacaggcagggaggggcatccctccctgccggcctcagggagcgaacgtggatgaaaaccacagggattccggatgccagaccccattttatacttcacttttctctacagtgttgttttgttgttgttggtttttattttttatactttggccataccacagagctagattgccc 581 203878_s_attgccagcgactgtctcagactgggcagggaggctttggcatgacttaagaggaagggcagtcttgggacccgctatgcaggtcctggcaaacctggctgccctgtctcatccctgtccctcagggtagcaccatggcaggactgggggaactggagtgtccttgctgtatccctgttgtgaggttccttccaggggctggcactgaagcaagggtgctggggccccatggccttcagccctggctgagcaactgggctgtagggcagggccacttcctgaggtcaggtcttggtaggtgcctgcatctgtctgccttctggctgacaatcctggaaatctgttctccagaatccaggccaaaaagttcacagtcaaatggggaggggtattcttcatgcaggagaccccaggccctggaggctgcaacatacctcaatcctgtcccaggccggatcctcctgaagcccttttcgcagcactgctatcctccaaagccattgtaaatgtgtgtacagtgtgtataaaccttcttcttctt 582 204006_s_atgagtacaggtgccagacaaacctctccaccctcagtgacccggtgcagctagaagtccatatcggctggctgttgctccaggcccctcggtgggtgttcaaggaggaagaccctattcacctgaggtgtcacagctggaagaacactgctctgcataaggtcacatatttacagaatggcaaagacaggaagtattttcatcataattctgacttccacattccaaaagccacactcaaagatagcggctcctacttctgcagggggcttgttgggagtaaaaatgtgtcttcagagactgtgaacatcaccatcactcaaggtttggcagtgtcaaccatctcatcattctctccacctgggtaccaagtctctttctgcttggtgatggtactcctttttgcagtggacacaggactatatttctctgtgaagacaaacatttgaagctcaacaagagactggaaggaccataaacttaaatggagaaaggaccctcaagacaaatgacc583 204051_s_ataaccagccagtcccaagaagaacattaaaactaggagtgcccagaagagaacaaacccgaaaagagtgtgagctaactagtttccaaagcggagacttccgacttccttacaggatgaggctgggcattgcctgggacagcctatgtaaggccatgtgccccttgccctaacaactcactgcagtgctcttcatagacacatcttgcagcatttttcttaaggctatgcttcagtttttctttgtaagccatcacaagccatagtggtaggtttgccctttggtacagaag584 204320_atgaaaatgtaccttggtgccaccaacccattttgtgccacatgcaagttttgaataaggatgtatggaaaacaacgctgcatatacaggtaccatttaggaaataccgatgcctttgtgggggcagaatcacagacaaaagctttgaaaatcataaagatataagttggtgtggctaagatggaaacagggctgattcttgattcccaattctcaactctccttttcctatttgaatttctttggtgctgtagaaaacaaaaaaagaaaaatatatattcataaaaaatatggtgctcattctcatccatccaggatgtactaaaacagtgtgtttaataaattgtaattattttgtgtacagttctatactgttatctgtgtccatttccaaaacttgcacgtgtccctgaattccgctgactctaatttatgaggatgccgaactctgatggcaataatatatgtattatgaaaatgaagttatgatttccgatgaccctaagtcc 585204475_atgaagaactgtctattttctcagtcatttttaacctctagagtcactgatacacagaatataatcttatttatacctcagtttgcatatttttttactatttagaatgtagccctttttgtactgatataatttagttccacaaatggtgggtacaaaaagtcaagtttgtggcttatggattcatataggccagagttgcaaagatcttttccagagtatgcaactctgacgttgatcccagagagcagcttcagtgacaaacatatcctttcaagacagaaagagacaggagacatgagtctttgccggaggaaaagcagctcaagaacacatgtgcagtcactggtgtcaccctggataggcaagggataactcttctaacaca 586204620_s_attgccgtgctcccaaaacattttaaatgaaagtattggcattcaaaaagacagcagacaaaatgaaagaaaatgagagcagaaagtaagcatttccagcctatctaatttctttagttttctatttgcctccagtgcagtccatttcctaatgtataccagcctactgtactatttaaaatgctcaatttcagcaccgatggccatgtaaataagatgatttaatgttgattttaatcctgtatataaaataaaaagtcacaatgagtttgggcatatttaatgatgattatggagccttagaggtctttaatcattggttcggctgcttttatgtagtttaggctggaaatggtttcacttgctctttgactgtcagcaagactgaagatggcttttcctggacagctagaaaacacaaaatcttgtaggtcattgcacctatctcagccataggtgcagtttgcttctacatgatgctaaaggctgcgaatgggatcctgatggaactaaggactccaatgtcgaactcttctttgctgc587 204811_s_atggggaactgagggcaaggggatatagtgatggggctcagatggactgggaggagggggagggtgatgcattaattaatggcttcgttaattaatgtcatgttgcttgtcgctttctcagtgtgtgtgtgtggtccatgcccactgctggtgccagggtgggtgtccatgtgcacccggcctggatgccagctgtgtccttcgggggcgtgcgtgtaactgtagtgtagtcaggtgctcaatggagaatataaacatatacagaaaaatatatattttaagtttaaaaaacagaaaaacagacaaaacaatccccatcaggtagctgtctaacccccagctgggtctaatccttctcattacccacccgacctggctgcccctcaccttgggctggggactggggggccatttccttttctctgccctttttttgttgttctattttgtacagacaagttggaaaaacaacagcgacaaaaaagtcaagaaactttgtaaaatatcgtgtgtgtgattccttgt588 205479_s_atcccgaccggtgggcatttgtgaggcccatggttgagaaatgaataatttcccaattaggaagtgtaagcagctgaggtctcttgagggagcttagccaatgtgggagcagcggtttggggagcagagacactaacgacttcagggcagggctctgatattccatgaatgtatcaggaaatatatatgtgtgtgtatgtttgcacacttgttgtgtgggctgtgagtgtaagtgtgagtaagagctggtgtctgattgttaagtctaaatatttccttaaactgtgtggactgtgatgccacacagagtggtctttctggagaggttataggtcactcctggggcctcttgggtcccccacgtgacagtgcctgggaatgtacttattctgcagcatgacctgtgaccagcactgtctcagtttcactttcacatagatgtccctttcttggccagttatcccttccttttagcctagttcatccaatcctcactgggtgggg589 205765_atcaccacctacctatgatgccgtggtacagatggagtaccttgacatggtggtgaatgaaacactcagattattcccagttgctattagacttgagaggacttgcaagaaagatgttgaaatcaatggggtattcattcccaaagggtcaatggtggtgattccaacttatgctcttcaccatgacccaaagtactggacagagcctgaggagttccgccctgaaaggttcagtaagaagaaggacagcatagatccttacatatacacaccctttggaactggacccagaaactgcattggcatgaggtttgctctcatgaacatgaaacttgctctaatcagagtccttcagaacttctccttcaaaccttgtaaagaaacacagatccccttgaaattagacacgcaaggacttcttcaaccagaaaaacccattgttctaaaggtggattcaagagatggaaccctaagtggagaatgagttattctaaggacttctactttggtcttcaagaaagctgtgccccagaacaccagagatttcaacttagtca 590 205828_atgaaaatcgatgcagccatttctgataaggaaaagaacaaaacatatttctttgtagaggacaaatactggagatttgatgagaagagaaattccatggagccaggctttcccaagcaaatagctgaagactttccagggattgactcaaagattgatgctgtttttgaagaatttgggttcttttatttctttactggatcttcacagttggagtttgacccaaatgcaaagaaagtgacacacactttgaagagtaacagctggcttaattgttgaaagagatatgtagaaggcacaatatgggcactttaaatgaagctaataattcttcacctaagtctctgtgaattgaaatgttcgttttctcctgcctgtgctgtgactcgagtcacactcaagggaacttgagcgtgaatctgtatcttgccggtcatttttatgttattacagggcattcaaatgggctgctgcttagcttgcaccttgtcacatagagtgatctttcccaagagaaggggaagcactcgtgtgcaacagac591 205927_s_attccacacacggccaggcctgtttatctacactgctgcccactcctctctccagctccacatgctgtacctggatcattctgaagcaaattccgagcattacatcattttgtccataaatatttctaacatccttaaatatacaatcggaattcaagcatctcccattgtcccacaaatgtttggctgtttttgtagttggattgtttgtattaggattcaagcaaggcccatatattgcatttatttgaaatgtctgtaagtctctttccatctacagagtttagcacatttgaacgttgctggttgaaatcccgaggtgtcatttgacatggttctctgaacttatctttcctataaaatggtagttagatctggaggtctgattttgtggcaaaaatacttcctaggtggtgctgggtacttcttgttgcatcctgtcaggaggcagataatgctggtgcctctctattggtaatgttaagactgctgggtgggtttggagttcttggc 592207173_x_atgaacatccaagtctttcttcttttttaagttgtcaaagaagcttccacaaaattagaaaggacaacagttctgagctgtaatttcgccttaaactctggacactctatatgtagtgcatttttaaacttgaaatatataatattcagccagcttaaacccatacaatgtatgtacaatacaatgtacaattatgtctcttgagcatcaatcttgttactgctgattcttgtaaatctttttgcttctactttcatcttaaactaatacgtgccagatataactgtcttgtttcagtgagagacgccctatttctatgtcatttttaatgtatctatttgtacaattttaaagttcttattttagtatacatataaatatcagtattctgacatgtaagaaaatgttacggcatcacacttatatttta593 207191_s_ataatctcttctagagcacctgctatccccaacttctagacctgctccaaactagtgactaggatagaatttgatcccctaactcactgtctgcggtgctcattgctgctaacagcattgcctgtgctctcctctcaggggcagcatgctaacggggcgacgtcctaatccaactgggagaagcctcagtggtggaattccaggcactgtgactgtcaagctggcaagggccaggattgggggaatggagctggggcttagctgggaggtggtctgaagcagacagggaatgggagaggaggatgggaagtagacagtggctggtatggctctgaggctccctggggcctgctcaagctcctcctgctccttgctgttttctgatgatttgggggcttgggagtccctttgtcctcatctgagactgaaatgtggggatccaggatggcttccttcctcttacccttcctccctcagcctgcaacctctatcctggaacctgtcctccctttctccccaactatgcatctgttgtctgctcct 594 208063_s_ataagaagctaagcctgatctcctgtaaaaacatcatttccctgatggacaccagcggcaatgggaagctggagtttgatgaattcaaagtgttctgggacaagctgaagcagtggattaaccttttccttcggtttgatgctgacaagtccggcaccatgtctacctatgaactacggactgcactgaaagctgcaggctttcagctgagcagccacctcctgcagctgattgtgctcaggtatgcggatgaggagctccagctggacttcgatgacttcctcaactgcctggtccggctggagaatgcgagccgggtgttccaggctctcagtacaaagaacaaggagttcattcatctcaatataaatgagttcatccatttgacaatgaacatctgaggctgccttgtagagatgcagcctgcccagctgaatcttggcttctggaccttgaccttcagaacttctcttggtgtggaaccattacgcccagggttcactc595 208782_atactcccaagagcaaatccacattcctcttgagttctgcagcttctgtgtaaatagggcagctgtcgtctatgccgtagaatcacatgatctgaggaccattcatggaagctgctaaatagcctagtctggggagtcttccataaagttttgcatggagcaaacaaacaggattaaactaggtttggttccttcagccctctaaaagcatagggcttagcctgcaggcttccttgggctttctctgtgtgtgtagttttgtaaacactatagcatctgttaagatccagtgtccatggaaacattcccacatgccgtgactctggactatatcagtttttggaaagcagggttcctctgcctgctaacaagcccacgtggaccagtctgaatgtctttcctttacacctatgtttttaagtagtcaaacttcaagaaacaatctaaacaagtttctgttgcatatgtgtttgtgaacttgtatttgtatttagtaggcttctatattgcatttaacttgtttttgtaactcctgattcttcct596 208850_s_atgaagcctcaagttccagtgcagagatcctacttctctgagtcagctgaccccctccccgcaatccctcaaaccttgaggagaagtggggaccccacccctcatcaggagttccagtgctgcatgcgattatctacccacgtccacgcggccacctcaccctctccgcacacctctggctgtctttttgtactttttgttccagagctgcttctgtctggtttatttaggttttatccttccttttctttgagagttcgtgaagagggaagccaggattggggacctgatggagagtgagagcatgtgaggggtagtgggatggtggggtaccagccactggaggggtcatccttgcccatcgggaccagaaacctgggagagacttggatgaggagtggttgggctgtgcctgggcctagcacggacatggtctgtcctgacagcactcctcggcaggcatggctggtgcctg 597 208851_s_ataaagcagcgctagtggagggttggagaaggaggtaaggatgagggttcatcatccctccctgcctaaggaagctaaaagcatggccctgctgcccctccctgcctccacccacagtggagagggctacaaaggaggacaagaccctctcaggctgtcccaagctcccaagagcttccagagctctgacccacagcctccaagtcaggtggggtggagtcccagagctgcacagggtttggcccaagtttctaagggaggcacttcctcccctcgcccatcagtgccagcccctgctggctggtgcctgagcccctcagacagccccctgccccgcaggcctgccttctcagggacttctgcggggcctgaggcaagccatggagtgagacccaggagccggacacttctcaggaaatggcttttcccaacccccagcccccacccggtggttcttcctgttctgtgactgtgtatag 598208937_s_atttcagccagtcgccaagaatcatgaaagtcgccagtggcagcaccgccaccgccgccgcgggccccacgtgcgcgctgaaggccggcaagacagcgagcggtgcgggcgaggtggtgcgctgtctgtctgagcagagcgtggccatctcgcgctgccggggcgccggggcgcgcctgcctgccctgctggacgagcagcaggtaaacgtgctgctctacgacatgaacggctgttactcacgcctcaaggagctggtgcccaccctgccccagaaccgcaaggtgagcaaggtggagattctccagcacgtcatcgactacatcagggaccttcagttggagctgaactcggaatccgaagttggaacccccgggggccgagggctgccggtccgggctccgctcagcaccctcaacggcgagatcagcgcc 599 209218_atgattccctgcatcaactaagaaaagcctgttttctttatttcaaacttggtggcgaatgtgttgcgggtcctgttgggctgctttctgtattgtctcctaaccctctagttttaattggacacttctttgctgttgcaatctatgccgtgtatttttgctttaagtcagaaccttggattacaaaacctcgagcccttctcagtagtggtgctgtattgtacaaagcgtgttctgtaatatttcctctaatttactcagaaatgaagtatatggttcattaagcttaaaggggaaccatttgtgaatgaatatttggaacttaccaagtcctaagagacttttggaagaggatatatatagcatagtaccataccacttata 600 209395_atgctgtggggatagtgaggcatcgcaatgtaagactcgggattagtacacacttgttgatgattaatggaaatgtttacagatccccaagcctggcaagggaatttcttcaactccctgccccctagccctccttatcaaaggacaccattttggcaagctctatcaccaaggagccaaacatcctacaagacacagtgaccatactaattataccccctgcaaagccagcttgaaaccttcacttaggaacgtaatcgtgtcccctatc 601 209396_s_attcaccaatgccatcaaggatgcactcgctgcaacgtagccctctgttctgcacacagcacgggggccaaggatgccccgtccccctctggctccagctggccgggagcctgatcacctgccctgctgagtcccaggctgagcctcagtctccctcccttggggcctatgcagaggtccacaacacacagatttgagctcagccctggtgggcagagaggtagggatggggctgtggggatagtgaggcatcgcaatgtaagactcgggattagtacacacttgttgatgattaatggaaatgtttacagatccccaagcctggcaagggaatttcttcaactccctgccccctagccctccttatcaaaggacaccattttggcaagctctatcaccaaggagccaaacatcctacaagacacagtgaccatactaattataccccctgcaaagccagcttgaaaccttcact 602 209596_attccaacctccttcaaattcagtcaccactgttatattaccttctccaggaaccctccagtggggaaggctgcgatattagatttccttgtatgcaaagtttttgttgaaagctgtgctcagaggaggtgagaggagaggaaggagaaaactgcatcataactttacagaattgaatctagagtcttccccgaaaagcccagaaacttctctgcagtatctggcttgtccatctggtctaaggtggctgcttcttccccagccatgagtcagtttgtgcccatgaataatacacgacctgttatttccatgactgctttactgtattttt603 209875_s_atgaatggtgcatacaaggccatccccgttgcccaggacctgaacgcgccttctgattgggacagccgtgggaaggacagttatgaaacgagtcagctggatgaccagagtgctgaaacccacagccacaagcagtccagattatataagcggaaagctaatgatgagagcaatgagcattccgatgtgattgatagtcaggaactttccaaagtcagccgtgaattccacagccatgaatttcacagccatgaagatatgctggttgtagaccccaaaagtaaggaagaagataaacacctgaaatttcgtatttctcatgaattagatagtgcatcttctgaggtcaattaaaaggagaaaaaatacaatttctcactttgcatttagtcaaaagaaaaaatgctttatagcaaaatgaaagagaacatgaaatgcttctttctcagtttattggttgaatgtgtatctatttgagtctggaaataactgatgtgtttgataattagtttagtttgtggcttcatggaa604 209955_s_atacagctttccaaggtgacaaactcctctatgcagtgtatcgaaagctgggtgtttatgaagttgaagaccagattacagctgtcagaaaattcatagaaatgggtttcattgatgaaaaaagaatagccatatggggctggtcctatggaggatacgtttcatcactggcccttgcatctggaactggtcttttcaaatgtggtatagcagtggctccagtctccagctgggaatattacgcgtctgtctacacagagagattcatgggtctcccaacaaaggatgataatcttgagcactataagaattcaactgtgatggcaagagcagaatatttcagaaatgtagactatcttctcatccacggaacagcagatgataatgtgcactttcagaactcagcacagattgctaaagctctggttaatgcacaagtggatttccaggcaatgtggtactctgaccagaaccacggcttatccggcctgtccacgaaccacttatacacccacatgacccacttcctaaagcagtg 605 210095_s_attcttttgtcctccttagcacaatgtaaaaaagaatagtaatatcagaacaggaaggaggaatggcttgctggggagcccatccaggacactgggagcacatagagattcacccatgtttgttgaacttagagtcattctcatgcttttctttataattcacacatatatgcagagaagatatgttcttgttaacattgtatacaacatagccccaaatatagtaagatctatactagataatcctagatgaaatgttagagatgctatatgatacaactgtggccatgactgaggaaaggagctcacgcccagagactgggctgctctcccggaggccaaacccaagaaggtctggcaaagtcaggctcagggagactctgccctgctgcagacctcggtgtggacacacgctgcatagagctctccttgaaaacagaggggtctcaagacattctgcctacctattagc 606 210511_s_ataaaggagcagtcgcacagacctttcctcatgctgcaggcccggcagtctgaagaccaccctcatcgccggcgtcggcggggcttggagtgtgatggcaaggtcaacatctgctgtaagaaacagttctttgtcagtttcaaggacatcggctggaatgactggatcattgctccctctggctatcatgccaactactgcgagggtgagtgcccgagccatatagcaggcacgtccgggtcctcactgtccttccactcaacagtcatcaaccactaccgcatgcggggccatagcccctttgccaacctcaaatcgtgctgtgtgcccaccaagctgagacccatgtccatgttgtactatgatgatggtcaaaacatcatcaaaaaggacattcagaacatgatcgtggaggagtgtgggtgctcatagagttgcccagc 607 211571_s_atacaagcatcctgtctcacgaagaacaaatgtttgttaatcgtgtgggccatgattatcagtggataggcctcaatgacaagatgtttgagcatgacttccgttggactgatggcagcacactgcaatacgagaattggagacccaaccagccagacagcttcttttctgctggagaagactgtgttgtaatcatttggcatgagaatggccagtggaatgatgttccctgcaattaccatctcacctatacgtgcaagaaaggaacagttgcttgcggccagccccctgttgtagaaaatgccaagacctttggaaagatgaaacctcgttatgaaatcaactccctgattagataccactgcaaagatggtttcattcaacgtcaccttccaactatccggtgcttaggaaatggaagatgggctatacctaaaattacctgcatgaacccatctgcataccaaaggacttattctatgaaatactttaaaaattcctcatcagcaaaggacaattcaataaatacatccaaacatgatcatcgttggagccggaggtgg 608 211966_attggtgatgtctgctactatgccagccggaacgacaagtcctactggctctctaccactgcgccgctgcccatgatgcccgtggccgaggacgagatcaagccctacatcagccgctgttctgtgtgtgaggccccggccatcgccatcgcggtccacagtcaggatgtctccatcccacactgcccagctgggtggcggagtttgtggatcggatattccttcctcatgcacacggcggcgggagacgaaggcggtggccaatcactggtgtcaccgggcagctgtctagaggacttccgcgccacaccattcatcgaatgcaatggaggccgcggcacctgccactactacgccaacaagtacagcttctggctgaccaccattcccgagcagagcttccagggctcgccctccgccgacacgctcaaggccggcctcatccgcacacacatcagccgctgccaggtgtgcatgaagaacctgtgagccggcgcgtgccaggaagggccattttggtgcttattcttaacttattacctcaggtgccaacccaaaa 609 211980_atgaaagactgtgctgtcctttaacataggtttttaaagactaggatattgaatgtgaaacatccgttttcattgttcacttctaaaccaaaaattatgtgttgccaaaaccaaacccaggttcatgaatatggtgtctattatagtgaaacatgtactttgagcttattgtttttattctgtattaaatattttcagggttttaaacactaatcacaaactgaatgacttgacttcaaaagcaacaaccttaaaggccgtcatttcattagtattcctcattctgcatcctggcttgaaaaacagctctgttgaatcacagtatcagtattttcacacgtaagcacattcgggccatttccgtggtttctcatgagctgtgttcacagacctcagcagggcatcgcatggaccgcaggagggcagattcggaccact610 211981_attcggctactcttttgtgatgcacaccagcgctggtgcagaaggctctggccaagccctggcgtcccccggctcctgcctggaggagtttagaagtgcgccattcatcgagtgtcacggccgtgggacctgcaattactacgcaaacgcttacagcttttggctcgccaccatagagaggagcgagatgttcaagaagcctacgccgtccaccttgaaggcaggggagctgcgcacgcacgtcagccgctgccaagtctgtatgagaagaacataatgaagcctgactcagctaatgtcacaacatggtgctacttcttcttctttttgttaacagcaacgaaccctagaaatatatcctgtgtacctcactgtccaatatgaaaaccgtaaagtgccttataggaatttgcgtaactaacacaccctgc 611 212344_atggaaaacacctcatttgaccttgccagctgaccttcaaaccctgcatttgaaccgaccaacattaagtccagagagtaaacttgaatggaataacgacattccagaagttaatcatttgaattctgaacactggagaaaaaccgaaaaatggacggggcatgaagagactaatcatctggnaaaccgatttcagtggcgatggcatgacagagctagagctcgggcccagccccaggctgcagcccattcgcaggcacccgaaagaacttccccagtatggtggtcctggaaaggacatttttgaagatcaactatatcttcctgtgcattccgatggaatttcagttcatcagatgttcaccatggccaccgcagaacaccgaagtaattccagcatagcggggaagatgttgaccaaggtggagaagaatcacgaaaaggagaagtcacagcacctagaaggcagcgcctcctcttcactctcctctgattagatgaaactgttaccttacccta612 212353_ataatatccttgttgtgtattaggtttttaaataccagctaaaggattacctcactgagtcatcagtaccctcctattcagctccccaagatgatgtgtttttgcttaccctaagagaggttttcttcttatttttagataattcaagtgcttagataaattatgttttctttaagtgtttatggtaaactcttttaaagaaaatttaatatgttatagctgaatctttttggtaactttaaatctttatcatagactctgtacatatgttcaaattagctgcttgcctgatgtgtgtatcatcggtgggatgacagaacaaacatatttatgatcatgaataatgtgctttgtaaaaagatttcaagttattaggaagcatactctgttttttaatca 613 212354_atgtgtgcacacggagactcatcgttataatttactatctgccaagagtagaaagaaaggctggggatatttgggttggcttggttttgattttttgcttgtttgtttgttttgtactaaaacagtattatcttttgaatatcgtagggacataagtatatacatgttatccaatcaagatggctagaatggtgcctttctgagtgtctaaaacttgacacccctggtaaatctttcaacacacttccactgcctgcgtaatgaagttttgattcatttttaaccactggaatttttcaatgccgtcattttcagttagatgattttgcactttgagattaaaatgccatgtctatttgattagtcttatttttttatttttacaggcttatcagtctcactgttggctgtcattgtgacaaagtcaaataaacccccaaggacgacacacagtatggatcacatattgtttgacattaagcttttgccagaaaatgttgcatgtgttttacctcgactt 614212488_atgaaaggcgatctcttcactgtgaaaagttgcccgggtgcagcgccttttccttctaccatgggaaatgcaggctgggcccttggggtgagcctgcggggctctggtgctgtccccgacccccaccaccaccagaatgcagttccagcttaggaagccacaaacaagccacccaggaggaacaaaacaccgccagcgtggattttccaaatttccctggaaagtaagtctcgctcttgccaaagaaaagtctggcttggagagtctctggagcccaggatgccagcatgtgccaatgactgtcaccttcatctcttcaaaagaaaagccatagccgaggactgtcccgcgacccccgtggactgcgtctaggtcatgtgattctgttttcatttctcatcccatccaatttgtccttttctcctgtcattttcttcctctgtggtcccttcaaagttgttataatttgtactgaacttcaaaatgtgtcccgttctccccagaccactctagccacagtatatt615 212489_atattgaaaagcaggtaccagtgccccttttcagacagtttttgattcgctctagacnttttttnttttttaatagggagggaaaaaatttgataattttcttntttctacatgcacttaagactaaaacacaggtttggattaattttatttgcttcctttttccgcttttcttcccgcagagcctgatgggagaatgtccagggcagggaaaccacattttttgtaggtgataactcaatgaaaattggtgcttattttttacacttctctcttgtggctctcttgtggtgctatctgttttaaggtctccttgaaggcgcactggggtccctggccatgcctcgttctccctgctttctttatcctgttattgcctccacagtctgttgccaaggactctaagatcaatgcacgtcactttcctttccactgggcaggatagccaagcacactccctcctgcgctctcccgccccggtgcgtccactcccgagggctgttatgaggactgggttgtgcctacttgatttgaaaacacacac616 213106_atacttctcagcaaataaatctcccttaagtaggaaanctagatttcatattngcttnctttgaattaacagcaactttccacaggtaaatctgttcttgcaaagatgtgagcagaatagttaaaaataatatttttatgtttcatggttctaaatggaagccataaatgcagtaaatactatctgttgtttaactactttaatcgtcattttttacattttcaagtttattaggttaagaaaaacagggcagccttggaaggcagctactacagaaaactgcagttttgcgttaaagataaagtagtattttcagctccctgaaaaaccattcctgctgaaactgctgtagaaattgtgaagctgcatgagtggagagtattgaatctgtggttatagtagttttctcaggtttgtttatcttgatgtttgatgcactgtgttttatagttattaaaattgagtaatattatttctatgcagtgttatgtgtcattggccttttgtgaatgtgcatgttttaaactgcaaattttaaacattttgtcctctaattgttat617 213125_atgaatgagtattcctatacgacccagatagactacaaccccaaggaccgcctgctctatgcctgggacaatggccaccaggtcacttaccatgtcatctttgcctactgacacccttgtccccacaagcagaagcacagaggggtcactagcaccttgtgtgtatgtgtgtgcgcgcacgtgtgtgtaggtgggtatgtgttgtttaaaaatatatattattttgtataatattgcaaatgtaaaatgacaatttgggtctatttttttatatggattgtagatcaatccatacgtgtatgtgctggtctcatcctccccagtttatatttttgtgcaaatgaacttctccttttgaccagtaaccaccttccttcaagccttcagcccctccagctccaagtctcagatctcgaccattgaaaaggtttcttcatctgggtcttgcaggaggcaggcaacac 618 213524_s_atgtgctcggcctgatggagactgtgtgcagccccttcacggccgccagacgtctgcgggaccaggaggcagccgtggcggagctgcaggccgccctggagcgacaggctctccagaagcaagccctgcaggagaaaggcaagcagcaggacacggtcctcggcggccgggccctgtccaaccggcagcacgcctcctaggaactgtgggagaccagcggagtgggagggagacgcagtagacagagacagaccgagaaggaagggagagacagagggggcgcgcgcacaggagcctgactccgctgggagagtgcaggagcacgtgctgttttttatttggacttaacttcagagaaaccgctgacatctagaactgacctaccacaagcatccaccaaaggagtttgggattgagtttntgctgctgtgcagcactgcattgtcatgacatttccaacactgtgtgaattatctaaatgcgtctaccattttgcactagggag619 213869_x_atcacagcctccaagtcaggtggggtggagtcccagagctgcacagggtttggcccaagtttctaagggaggcacttcctcccntcgcccatcagtgccagcccctgctggctggtgcctgagcccctcagacagccccctgccccgcaggcctgccttctcagggacttctgcggggcctgaggcaagccatggagtgagacccaggagccggacacttctcaggaaatggcttttcccaacccccagcccnccacccggtggttcttcctgttctgtgactgtgtatagtgccaccacagcttatggcatctcattgaggacaaagaaaactgcacaataaaaccaagcctctggaatctgtcctcgtgtccacctggccttcgctcctccancagtgcctgcctgnccccncttcgctggggtctccacgggtgaggctggggaacgccacctcttcctcttccctgacttctccccaaccacttagtagcaacgctaccccaggggctaatgactgcacactgggcttcttttcagaatgaccctaacgagacacatttgcccaaa 620 213905_x_atcacaaaaccccagggacagcggtctccccagcctgccctgctcangccttgcccccaaacctgtactgtcccggaggaggttgggaggtggaggcccagcatcccgcgcagatgacaccggttttcctagaagcccctcacccccactggcccactggtggctaggtctccccttatccttctggtccagcgcaaggaggggctgcttctgaggtcggtggctgtctttccattaaagaaacaccgtg 621 214234_s_atgaatgaagaaaagtcgcctcaacgacaaacaaaagcaccgactagatttccttcagctgatgattgactcccagaattcgaaagaaactgagtcccacaaagctctgtctgatctggagctcgcagcccagtcaataatcttcatttttgctggctatgaaaccaccagcagtgttctttccttcactttatatgaactggccactcaccctgatgtccagcagaaactgcaaaaggagattgatgcagttttgcccaata 622 214235_atggtgaggggatgacccctggagatgaagggaagaggtgaagccttagcaaaaatgcctcctcaccactccccaggagaatttttataaaaagcataatcactgattccttcactgacataatgtaggaagcctctgaggagaaaaacaaagggagaaacatagagaacggttgctactggcagaagcataagatctttgtacaatattgctggccctggttcacctgtttactgttatcacaata 623 214247_s_atacttaggtaattgtagggcgaggattataaatgaaatttgcaaaatcacttagcagcaactgaagacaattatcaaccacgtggagaaaatcaaaccgagcagggctgtgtgaaacatggttgtaatatgcgactgcgaacactgaactctacgccactccacaaatgatgttttcaggtgtcatggactgttgccaccatgtattcatccagagttcttaaagtttaaagttgcacatgattgtataagcatgctttctttgagttttaaat 624215646_s_attctcacctatacgtgcaagaaaggaacagttgcttgcggccancccctgttgtagaaaatgccaagacctttggaaagatgaaacctcgttatgaaatcaactccctgattagataccacntgcaaagatggtttcattcaacgtcaccttccaactatccggtgcttaggaaatggaagatgggctatacctaaaattacctgcatgaacc625 217430_x_atagggcctaagggtgacagaggtgatgctggtcccaaaggtgctgatggctctcctggcaaagatggcgtccgtggtctgaccggccccattggtcctcctggccctgctggtgcccctggtgacaagggggaccccattcccgaggagctttatgag 626 217763_s_ataacattgtaatggccatcgctggaaacaagtgcgacctctcagatattagggaggttcccctgaaggatgctaaggaatacgctgaatccataggtgccatcgtggttgagacaagtgcaaaaaatgctattaatatcgaagagctctttcaaggaatcagccgccagatcccacccttggacccccatgaaaatggaaacaatggaacaatcaaagttgagaagccaaccatgcaagccagccgccggtgctgttgacccaagggcgtggtccacggtacttgaagaagccagagcccacatcctgtgcactgctgaaggaccctacgctcggtggcctggcacctcactttgagaagagtgagcacactggctttgcatcctggaaggcctgcagggggcggggcaggaaatgtacctgaaaaggattttagaaaaccctgggaaacccaccacaccaccacaaaatggcctttagtgt627 218211_s_atgccacaccttcgcgaaacctgtggtggcccaccagtcctaacgggacaggacagagagacagagcagccctgcactgttttccctccaccacagccatcctgtccctcattggctctgtgctttccactatacacagtcaccgtcccaatgagaaacaagaaggagcaccctccacatggactcccacctgcaagtggacagcgacattcagtcctgcactgctcacctgggtttactgatgactcctggctgccccaccatcctctctgatctgtgagaaacagctaagctgctgtgacttccctttaggacaatgttgtgtaaatctttgaaggacacaccgaagacctttatactgtgatcttttacccctttcactcttggctttcttatgttgc628 218638_s_atctgccccgagctcgaagaagaggctgagtgcgtccctgataactgcgtctaagaccagagccccgcagcccctggggcccccggagccatggggtgtcgggggctcctgtgcaggctcatgctgcaggcggccgaggcacagggggtttcgcgctgctcctgaccgcggtgaggccgcgccgaccatctctgcactgaagggccctctggtggccggcacgggcattgggaaacagcctcctcctttcccaaccttgcttcttaggggcccccgtgtcccgtctgctctcagcctcctcctcctgcaggataaagtcatccccaaggctccagctactctaaattatggtctccttataagttattgctgctccaggagattgtccttcatcgtccaggggcctggctcccacgtggttgcagatacctcagacctggtgctctaggctgtgctgagcccactctcccgagggcgcatccaagcgggggccacttgagaagtgaataaatggggcggtttcggaagcgtcagtgtttccatgttatgg 629 219955_atgaagttgcaacattcgtttgataggaattccagaaaaggagagttatgagaatagggcagaggacataattaaagaaataattgatgaaaactttgcagaactaaagaaaggttcaagtcttgagattgtcagtgcttgtcgagtacctagtaaaattgatgaaaagagactgactcctagacacatcttggtgaaattttggaattctagtgataaagagaaaataataagggcttctagagagagaagagaaattacctaccaaggaacaagaatcaggttgacagcagacttatcactggacacactggatgctagaagtaaatggagcaatgtcttcaaagttctgctggaaaaaggctttaatcctagaatcctatatccagccaaaatggcatttgattttaggggcaaaacaaaggtatttcttagtattgaagaatttagagattatgttttgcatatgcccaccttgagagaattactggggaataatataccttagcacgccagggtgactaca630 221011_s_atgagtggttcatccatactctcattccctcgcctccccttgtggacgggggtcttgccttttcaattcctgtgttttggtgtcttcccttatctgctaccctgaatcacctgtcctggtcttgctgtgtgatgggaacatgcttgtaaactgcgtaacaaatctactttgtgtatgtgtctgtttatgggggtggtttattatttttgctggtccctagaccactttgtatgaccgtttgcagtctgagcaggccaggggctgacagctaatgtcaggaccctcagcggtggagcctgctggggggacccagctgctcttggacaagtggctgagctcctatctggcctcctcttttttttttttttcaagtaatttgtgtgtatttctaactgattgtattgaaaaaattcctagtatttcagtaaaaatgcctgttgtgagatgaacctcctgtaacttctatctgttcttttttgaggctcaggga 631 221729_attggaattagaccatttggcctttgaactttcataggaaaaatgacccaacatttcttagcatgagctacctcatctctagaagctgggatggacttactattcttgtttatattttagatactgaaaggtgctatgcttctgttattattccaagactggagataggcagggctaaaaaggtattattatttttcctttaatgatggtgctaaaattcttcctataaaattccttaaaaataaagatggtttaatcactaccattgtgaaaacataactgttagacttcccgtttctgaaagaaagagcatcgttccaatgcttgttcactgttcctctgtcatactgtatctggaatgctttgtaatacttgcatgcttcttagaccagaacatgtaggtccccttgtgtctcaatactttttttttcttaattgcatttgttggctctattttaattt 632 221730_attagattccggtatatcgttcttcaagacacttgctctaagcggaatggaaatgtgggcaagactgtctttgaatatagaacacagaatgtggcacgcttgcccatcatagatcttgctcctgtggatgttggcggcacagaccaggaattcggcgttgaaattgggccagtttgttttgtgtaaagtaagccaagacacatcgacaatgagcaccaccatcaatgaccaccgccattcacaagaactttgactgtttgaagttgatcctgagactcttgaagtaatggctgatcctgcatcagcattgtatatatggtcttaagtgcctggcctccttatccttcagaatatttattttacttacaatcctcaagttttaattgattttaaatatttttcaatacaacagtttaggtttaagatgaccaatgacaatgaccacctt 633 221731_x_attttcagcaccgatggccatgtaaataagatgatttaatgttgattttaatcctgtatataaantaaaaagtncncaatgagtttngggcatatttaatgatgattatggagccttagaggtctttaatcattggttcnggctgcttttatgtagtttaggctggaaatggtttcacttgctctttgactgtcagcaagactgaagatggcttttcctggacagctagaaaacacaaaatcttgtaggtcattgcacctatctcagccataggtgcagtttgcttctacatgatgctaaaggctgcgaatgggatcctgatggaactaaggactccaatgtcgaactcttctttgctgcattcctttttcttcacttacaagaaaggcctgaatggaggacttttctgtaaccaggaacattttttaggggtcaaagtgctaataattaactcaaccaggtctactttttaatggctttcataacactaactcataaggttaccgatcaatgcatttcatacggatatagacctagggctctggagggtgggg634 221874_atctggcctacgtgttcaattttctatgaacaaaggctttagtccttgacccagggctaaagtggtctgtccaagctgttgttggtagagggagtatgataaaatgtttaaatctcatttggttaccttgagtcctggaacacgcagtaactgtcatgctatagtcntcatctgtatttggctgggaatacaaatgaagattgtggtgtattcaagcagtagggtttttgcttttgtttttgttttagtgccaacaaaacttttttttgtctgactacattaaagataagactgactatatttatacaacagaaactttgtaatagattttttcagctttgtgaaatcgaattttttttcatcagggctggttggatttcctttttaccctgtaatccaagcgttaatagtttgttagaagatgggttattgcatgtcactt635 223969_s_atgaagatcaaggatgttctcaacagtctagagtacagtccctctcctataagcaagaagctctcgtgtgctagtgtcaaaagccaaggcagaccgtcctcctgccctgctgggatggctgtcactggctgtgcttgtggctatggctgtggttcgtgggatgttcagctggaaaccacctgccactgccagtgcagtgtggtggactggaccactgcccgctgctgccacctgacctgacagggaggaggctgagaactcagttttgtgaccatgacagtaatgaaaccagggtcccaaccaagaaatctaactcaaacgtcccacttcatttgttccattcctgattcttgggtaataaa 636 223970_atggagctcagagatctaagctgctttccatcttttctcccagccccaggacactgactctgtacaggatggggccgtcctcttgcctccttctcatcctaatcccccttctccagctgatcaacccggggagtactcagtgttccttagactccgttatggataagaagatcaaggatgttctcaacagtctagagtacagtccctctcctataagcaagaagctctcgtgtgctagtgtcaaaagccaaggcagaccgtcctcctgccctgctgggatggctgtcactggctgtgcttgtggctatggctgtggttcgtgggatgttcagctggaaaccacctgccactgccagtgcagtgtggtggactggaccactgcccgctgctgccacctgacctgacagggaggaggctgagaactcagttttgtgaccatgacagtaatgaaaccagggtcccaaccaagaaatctaactcaaacgtcccact 637224724_atgcctgagaaagcaagcacgcactctcagtcaacatgacagattctggaggataaccagcaggagcagagataacttcaggaagtccatttttgcccctgcttttgctttggattatacctcaccagctgcacaaaatgcattttttcgtatcaaaaagtcaccactaaccctcccccagaagctcacaaaggaaaacggagagagcgagcgagagagatttccttggaaatttctcccaagggcgaaagtcattggaatttttaaatcataggggaaaagcagtcctgttctaaatcctcttattcttttggtttgtcacaaagaaggaactaagaagcaggacagaggcaacgtggagaggctgaaaacagtgcagagacgtttgacaatgagtcagtagcacaaaagagatgacatttacctagcactataaaccctggttgcctctgaagaaactgccttcattgtatatatgtgactatttacatgtaatcaacatgggaacttttaggggaacctaataagaaatcccaattttcaggagtggtggtgtcaataaacgctctgtggccagtg 638 225664_atggaacccagagctgctgtgtatttcgagcgggcagtttatcttttgctatacttattttcaattcaattacaccacgattcaaataattcccctcctaaaaccaaaaaggagggaaacgtcaactccattgcaattacttatcttcctcttctatctctgttatacgccggggcatagaatgctcgtatacatctctttaacaaccacaaaccttaagccatgtagatgaagttagtgcatcaacgggatacagttccatattgccttaaacctccttgttttagacacactaacatttataccaaattgcagattattctgcagagagggaattgcatgtttgtgttgta 639 225681_ataattaatattcatcgcacttcttctgtggaaggactttgtgaaggaattggtgctggattagtggatgttgctatctgggttggcacttgttcagattacccaaaaggagatgcttctactggatggaattcagtttctcgcatcattattgaagaactaccaaaataaatgctttaattttcatttgctacctctttttttattatgccttggaatggttcacttaaatgacattttaaataagtttatgtatacatctgaatgaaaagcaaagctaaatatgtttacagaccaaagtgtgatttcacactgtttttaaatctagcattattcattttgcttcaatcaaaagtggtttcaatattttttttagttggttagaatactttcttcatagtcacattctctcaacctataatttggaatattgttgtggtcttttgttttttctcttagtatagcatttttaaaaaaatataaaagctaccaatctttgtacaatttg 640 225799_ataaatgactggatggtcgctgctttttaagtttcaaattgacattccagacaagcggtgcctgagcccgtgcctgtcttcagatcttcacagcacagttcctgggaaggtggagccaccagcctctccntgaataactgggagatgaaacaggaagctctatgacacacttgatcgaatatgacagacacngaaaatcacgactcanccccctccagcacctctacctgttgcccgccgatcacagccggaatgcagctgaaagattccctggggcctggttccaaccgcccactgtggactctgaggcctctgcatttgcgggtggtctgcctgtgatattttggtcatgggctggtctg 641 226237_atgaagaggagcaacatctatgccaaatactgtgcattctacaatggtgctaatctcagacctaaatgatactccatttaatttaaaaaagagttttaaataattatctatgtgcctgtatttcccttttgagtgctgcacaacatgttaacatattagtgtaaaagcagatgaaacaaccacgtgttctaaagtctagggattgtgctataatccctatttagttcaaaattaaccagaattcttccatgtgaaatggaccaaactcatattattgttatgtaaatacagagttttaatgcagtatgacatcccacaggggaaaagaatgtctgtagtgggtgactgttatcaaatattttatagaatacaatgaacggtgaacagactggtaacttgtttgagttcccatgacagatttgagacttg642 226248_s_attgaaagtgggcatctctgcaggcacctgtactgccatcctgctcaccgtcttgacctgctacttttggaaaaagaatcaaaanctagagtacangtactccangctggtgatgaatgctactctcaaggactgnnnnntnncngnngctgacagctgcgccatcatggnanncnnnnangnanngnnnnnnnncancnnnnnncanntgcgccatcatggaaggcgaggatgtagaggacgacctcatctttaccagcaagaagtcactctttgggaagatcaaatcatttacctccaagaggactcctgatggatttgactcagtgccgctgaagacatcctcaggaggcccagacatggacctgtgagaggcactgcctgcctcacctgcctcctcaccttgcatagcacctttgcaagcctgcggcgatttgggtgccagcatcctgcaacacccactgctggaaatctcttcattgtggccttatcagatgtttgaatttcagatctttttttatagagtacccaaaccctcctttctgcttgcctcaaacctgccaaatatacccacac 643 226311_ataaacgacgcaaatctctgagctggggaccacttggagaaccggcttagtaacagtcctgatcttcgcaagccagcttcttctgcatctgaggggctcctggcgcccagaggaggcagacagatgtcttctagctgagtttctaaccgcatgatgagactcagaccttccgctgcactagaaaatctgcaacagtgtccctgagtcacttctccttagtgggcagactcgtgttagatttgtggaacccagctctctgatttactccttttggaaaacccatggaatttcatgtataaggctttcatttgtattttaaggtttttctgtttgttttgagtatatacatggtgctcaatagcaacatcttagcagatgaagcagtttatgattccactccctcctgtatgacaggtagccactatactgaatcaaggtgctgaactcaaatcacaaaattctggcttaccgatacaacaaccaatac 644 226777_attataaggtaactctttagtcctccatttagcacattttaaatcctccaaagaataagtatcatgtgattattttagctttacaaaaaaaaagttgaatggcgttttattttcatggcctataagcaggtaccttagtagggcagatataggaaaaacaaattagagcaaaacaaatcctctacaaatccaaggcaggaaaagtggtggcagagtgactcattctcctgtccctcccatcaggtcaaatcaggaggctgcagtgaatgcctgttctttgaatgtgtagcagttgttncctgtaactctttaaaacttggctataggctgtttagcacagtacagattaaagatacagttacgtaaacagcaaagtaattttatagtgcttcatccatttatcatgctttggtttgctaattttttcacatacctttttctatcacagtctgttgcttttgtacacatttctcatattggggttcgaca 645 226930_atggtgccaggaaggtcacagatggacactggccattctggtcatctcagtctggaactcagtcccacttcttggcctggacaatgaacaggattcagttttgctgttaactttgcttctctacttttttttgtttgtttgtaatagcacatcccagagacatcagaaaccagcaactgattcagtgtgatttccagactttttaggcatgaaattcggacacttcagtatttccaggaatagcatatgcacgctgttcttgcttcatggaatgctacatgctttctgtttttctcattttggatttctccaaaactaactgaatttaagcttcaggtccctttgtatgcagtagaaaggaattattaaaaacaccaccaaagaaaataaatatatcctacttgaaatttactctatggacttacccactgctagaataaatgtatcaaatcttatttgtaaattctcaattttgatatatatatgtatatatgcatatacatatccacacttgtctgcaag646 227140_atttaccctctatttaaatgctttgaaaaacagtgcattgacaatgggttgatatttttctttaaaagaaaaatataattatgaaagccaagataatctgaagcctgttttattttaaaactttttatgttctgtggttgatgttgtttgtttgtttgtttctattttgttggttttttactttgttttttgttttgttttgttttgttttgcatactacatgcagttctttaaccaatgtctgtttggctaatgtaattaaagttgttaatttatatgagtgcatttcaactatgtcaatggtttcttaatatttattgtgtagaagtactggtaatttttttatttacaatatgtttaaagagataacagtttgatatgttttcatgtgtttatagcagaagttatttatttctatggcattccagcggatattttggtgtttgcgaggcatgcagtcaatattttgtacagttagtggacagtattcagcaacgcctgatagcttctttggcctt 647 227566_atccacacaccaggcactaatcacctggtgaggatttggcatatccaccaaaaaatgcatccgatttaaccaacatctccaccagcgctacggactcctcccaattctgacatctcttgcagacaatactatgctctctacacactgtttagaaatggaaaggtgatctgcactgtatcttgggtttgttggctatgcttcctttgatgacatatattatacagtatatatatacatatattttttttgttagagttctagccattttatttctccgcagggtcctttctcagacattactgcatgctgtatatggcgttagctgtgtgttgatcttctaaaagatgatagagtttactggtaattgtgtaatcagctcctgcctttttatt 648 227676_atcaggaaactcttctctgacttggggagttcctacgcganacaactgggcttccgggacagctgggtcttcataggagccaaagacctcaggggtaaaagcccctttgagcagttcttaaagaacagcccagacacaaacaaatacgagggatggccagagctgctggagatggagggctgcatgcccccgaagccattttagggtggctgtggctcttcctcagccaggggcctgaagaagctcctgcctgacttaggagtcagagcccggcaggggctgaggaggaggagcagggggtgctgcgtggaaggtgctgcaggtccttgcacgctgtgtcgcgcctctcctcctcggaaacagaaccctcccacagcacatcctacccggaagaccagcctcagagggtccttctggaaccagctgtctgtggagagaatggggtgctttcgtcagggactgctgacggctggtcctgaggaaggacaaactgcccagacttgagcc649 227719_atcacttgatagactgtaagcacctgcttaactttgtgtcccaaatatttagtgtgtatatatatatatatatanncncacacacacacatatatattcaacaaataaagcaaaatataacatgcatttcacattttgtctttccctgttacgattttaatagcagaactgtatgacaagtttaggtgatcctagcatatgttaaattcaaattaatgtaaaacagattaacaacaacaaagaaactgtctatttgagtgaagtcatgctttctattataataacttggcttcggttatccatcaaatgcacacttatactgttatctgattg650 229218_atgccaaaaggcctggcttctgataggaaactggtaagaaactcttcatgaaaacacatcactaatattcgctattactctcctggtctgaagtcagcttttctgaaccattaaggtatttcatcacaagttatattttataatatcagtttaagaggcttttattcatgtgaacaccagnnccctttcaggggcatggtctttttgaaaaaaaaaaaanaaaaaaannaacagttttagccacatatcagatatttctatatctaattatcctttatggctaacattctgcctccattgttaaggtataattgttcctgaatttaaaggtggtttggcctctaatttaattctgattcagactctcctgtcaggactcaagaaaatttaattaattaccaaggattaagtcttctggttaaggtttctgggaaaaaaaaatagcaaagatgttgatttcttggaatccttttacaggttcataacagaaaaatcttcattccctgtaggcatttaattaaacctagttgagaagtgtgtgggattcctcaattatgaacaaaacacgtatattggctttcttt 651 229802_atgacatgattgtctataatctcgctagccttgtactgtgtgtgcatagcaattacagggaagtaatctagctcctgactattatgttgaactatgtcgctgctttttacaaacttgtcttgatccaaagcagtcacaatgataaccctgcatatctgggaatcataagtcaactatgtatctctgtgtgtgtatatatatgtatgtatgtatctattttcaaactgtgatttaatatttaaatattcctactgccatttttgtgactgaaaaactacacatgaggaaacgtcttagaattttccaatagaggaaaaataacacttgggcaatctgtcatgtttcacaacagttctcatttttctcatgatttgtgtagcgtggaatgtgtttgctcaatgtgaagggttttcattgctcaatttctctgtgtaa652 231766_s_atggttccggctaacacattttctaagtcgccagtgctgcttacagtttgaatacatgaaaatcctgtttctnagatgtttgcgcacgtgcttattaggaaatgagtctgtatggaaatctcaccacagataatggttaacgaaccgggtcgacatcacaaaggagggtggagactctttttactaacttgaatgagacaaaagcagtggtgtcagtttataatcctgatgcatttcagtaataatgtagaaaaacattattttaaaaaagttccaacacacagccatgaggagccnnnnnnnnnntcagttttgaaagaggtgcataataaaactactaaccagaggagtctatgccatttt 653 231832_atgagtttcaactttaaatgttcactatgtcatttagtgtccanctttacggataggttgactatctaaataggcatttttagtcattaaaaaaaantctagtcaccaggaggatccctataactcaaaataacttgtttgtaaaagaaaatttgtttacttacccattagtaagttcctgcatattcattataagatggcaaatcaaacttttctaggatgaagacagcttatttttaagttgtatagtcttagttggtttagggtctcaattttaattaataaaatacttggtttttatttgcttgtccttttgaattcctgttttaataattttaaaatgagcacaaagaangttgaagttcagattaatctcttctgaatgatgtttttttcctctgtgatgagttgtttctg654 231879_attgctgtagtcactggtgttcctcacccaccagctgtaactcagtttgtgtgaggtacagccacagaagatgtcatgtactgtatattacctggtgatagttgcttttcaccccccgagttcagtttctaggagccaatgaaacttcccctcacctcctcatctttccaagttgttctttgaattgaggagtttgaaggcataaacagttacttggggatttgcgaaaatcctacttagttactgcgtttacagttctttggcccagtctctgacccttcccnagtatttgtgcnatgattgtgtttactgctggatttttgaaggttttttttttnnagaaagtgccatttcattatttgatt 655 232176_atgggatcactgggagaagccatggcattatcttcaggcaatttagtctgtcccaaataaaataaatccttgcatgtaaatcattcaagggttatagtaatatttcatatactgaaaagtgtctcataggagtcctcttgcacatctaaaaaggctgaacatttaagtatcccgaattttcttgaattgctttccctatagattacaattggatttcatcatttaaaaaccatacttgtatatgtagttataatatgtaaggaatacattgtttataaccagtatgtacttcaaaaatgtgtattgtcaaacatacctaactttcttgcaataaatgcaaaagaaactggaacttgacaattataaatagtaatagtgaagaaaaaatagaaaggttgcaattatataggccatgggtggctcaaaactttgaa656 232458_atgattcctggattgatgtcttatctacaggcttctttttaaaaatnnnnnnngattggctgtgagtttaccaggattatagttgaggctaaaggacagctcctcaggaaagcccctgttctacatctacggtcacatgctggaccttgagttgtcactcagagaaaagagtgccatctaccgaaactccacagtttccattgtgaatggcttctttggtgcagagttccaaaaattatgtagcccagctctttaattttgtaacatctaatgatatcaccgccttgaagtgattaaagtagattgcttaaagaattaaagctttaaagatgaaagatgttattgcttttgctggacatgaggaacagttgtaaagtttccaggtctacaataactttctgganccctctcagtgaactgtttcttgta657 232481_s_atgaagtccatcctttggtccaaagcatctggaagaggaagaagagaggaatgagaaagaaggaagtgatgcaaaacatctccaaagaagtcttttggaacaggaaaatcattcaccactcacagggtcaaatatgaaatacaaaaccacgaaccaatcaacagaatttttatccttccaagatgccagctcattgtacagaaacattttagaaaaagaaagggaacttcagcaactgggaatcacagaatacctaaggaaaaacattgctcagctccagcctgatatggaggcacattatcctggagcccacgaagagctgaagttaatggaaacattaatgtactcacgtccaaggaaggtattagtggaacagacaaaaaatgagtattttgaacttaaagctaatttacatgctgaacctgactatttagaagtcctggagcagcaaacatagatggagagtttgagggctttcgcagaaatgctgtgattctgttttaagtccataccttgtaaataagtgccttacgtgagtgtgtcatcaatcagaacctaagc 658 233555_s_atgctgctcaagcgcctgcagaacaacgacacgtgcagcatgccaggcctcacgtgcttcacccacgacaaccagcactggcagacggcgcctttctggacactggggcctttctgtgcctgcaccagcgccaacaataacacgtactggtgcatgaggaccatcaatgagactcacaatttcctcttctgtgaatttgcaactggcttcctagagtactttgatctcaacacagacccctaccagctgatgaatgcagtgaacacactggacagggatgtcctcaaccagctacacgtacagctcatggagctgaggagctgcaagggttacaagcagtgtaacccccggactcgaaacatggacctgg 659 234994_atacaatcggctaaccttgacatttctttttaccttcatatgccactatctcggtagttcaaaaaaatttagttcttgataaattgccttgaagtttaccttgtgctggagagccttatgataactccaaagactttcttacggtataatacatgttgtttaggattgtgtttcttagtcactgaagataataaatattaaaatggatgttttcatcagaaaattttcatgttttcctttaaggtaacataattgtaagaattgtttaataaaatactcaggaaattctaaaggtttctccnaatacctaaacatttctgaacatcagtattgcagttgtggaagagcagaaggaggatacatttgtttgtgttgctccccaaaattccaccttgcatttgcatcacaaacttccctcaattgaggcagttttctttg660 235976_atcagtgctgctgtgaactaaagtatgtcatttatgctcaaagtttaattcttcttcttgggatattttaaaaatgctactgagattctgctgtaaatatgactagagaatatattgggtttgctttatttcataggcttaattctttgtaaatctgaatgaccataatagaaatacatttcttgtggcaagtaattcacagttgtaaagtaaataggaaaaattattttatttttattgatgtacattgatagatgccataaatcagtagcaaaaggcacttctaaaggtaagtggtttaagttgcctcaanagagggacaatgtagctttattttacaagaaggcatagttagatttctatgaaatatttattctgtacagttttatatanttttggttcacaaaagtaattattcttgggtgcctttcaa661 236894_ataaagtatattgtgctagcttgtctaagaataaacttnnatactgttgggggagggctgcacctgtcaagataacctgtcaatgtagtaggaaaacaggaggggacagtaacagaaaagcacgggaaaagatggcaaggttagttaaaatagaaaagtgctcagttcctcatacctgtaatcccagcagtttagggggccaaggaaggtgggtcacttgagcccaagagttcaaggccatcctgggcaatgtggcgaaagtgtctacaaaaaaatacaaaaagaggaagaaatgatatttcacaagtttgtatcatttgtcat 662 237521_x_atcagtccaaaatccatagacacagacagtagaaaggtggttatncaagggnctggtaggagagggagttagtatttagtggtatagagttttagtgtttnccgggtaaaaatgttnctagagatctgttgcaaccatgtgaatatacttaacactaccgtactgtacactgaaaaaatggttaagaggataaatttaaatggttaagaggaaaaatggttaagaggataatgttgttttgttaccacagtagtaacttttaaaaaccctcatgtatgttcttt663 37892_atcaacccattttgtgccacatgcaagttttgaataaggatggtatagaaaacaacgctgcatatacaggtaccatttaggnannancngatgcctttntgggggcagaatcacatggcaaaagctttgaaaatcataaagatataagttggtgtggctaagatggaaacagggctgattcttgattcccaattctcaactctccttttcctatttgaatttctttggtgctgtagaaaacaaaaaaagaaaaatatatattcataaaaaatatggtgctcattctcatccatccaggatgtactaaaacagtgtgtttaataaattgtaattattttgtgtacagttctatactgttatctgtgtccatttccaaaacttgcacgtgtccctgaattcc

TABLE 7 MSP primers and PCR conditions Re-anneal Gene Probe set GeneName Forward primer 5′-3′ Reverse primer 5′-3′ Temp CA4 206208_atCarbonic anhydrase TCGTTTTTCGCGTTTAGTT GCGCACCGAAAAAACCG 61.0° C. IV GTC(SEQ ID NO: 664) (SEQ ID NO: 665) CXCL12 209687_at Chemokine, CXCCGGTTACGGTTAGTATTCG AAAATACGACGATAAAAA 64.0° C. Motif, Ligand 12 GTTTC(SEQ ID NO: 666) ACGCG (SEQ ID NO: 667) DF 205382_s_at complement factorD CGAGGGTTTTTTAGCGATT AAACGAACCGCTCCCCG 64.0° C. TGTC (SEQ ID NO: 668)(SEQ ID NO: 669) MAMDC2 228885_at MAM domain- TTCGGCGTTTTCGTTTTTTACCCCTTAACAACATAATCG 60.0° C. containing protein C (SEQ ID NO: 670) CG(SEQ ID NO: 671) 2 precursor MT1M 217546_at Metallothionein-1MGATGGTGCGTTCGGTATTT GCTTACACCCGCCCGACTA 62.0° C. ATGT (SEQ ID NO: 672)(SEQ ID NO: 673) CAGE Control unbiased GTTTTGTGATTGGTTAGGTCCRTCACCTTCTACACCAA 61.0° C. amplification assay TATTAAAGT (SEQ IDAAAATA (SEQ ID NO: 675) NO: 674)

TABLE 8 COBRA Primers and PCR conditions Re-anneal Temp, Gene Probe setGene Name Forward primer 5′-3′ Reverse primer 5′-3′ Enzyme ADAMDECI206134_at ADAM-like, TGTGGATTTATTTTTATAA ATAACTCATTAAAAACT 61.0° C.decysin 1 GGATATTGAAT (SEQ ID CACATCTAAACACTA BstU I NO: 676) (SEQ IDNO: 677) GPM6B 209170_s_at Neuronal membrane TTAAGAAAGAGAGTAAGAAAATCCCAATTAAAAA 60.0° C. glycoprotein M6-b GAGGAAGAGTT (SEQ ID ACAACCA(SEQ ID Hinf I NO: 678) NO: 679) P2RY14 206637_at Purinergic receptorCAAAATAATAAATCCCTC GGAGGAAAGGAATTAG 60.0° C. P2Y, G-proteinTACTACTATTATCAA TTTAGAAGTTAGTT Acl I coupled, 14 (SEQ ID NO: 680) (SEQID NO: 681)

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1. A method of screening for the onset or predisposition to the onset ofa large intestine neoplasm or monitoring the progress of a neoplasm inan individual, said method comprising assessing the level of expressionof one or more genes or transcripts selected from: (i) the gene, genesor transcripts detected by Affymetrix probeset ID: and/or (ii) in abiological sample from said individual wherein a lower level ofexpression of the genes or transcripts of group (i) and/or group (ii)relative to control levels is indicative of a neoplastic large intestinecell or a cell predisposed to the onset of a neoplastic state. 2-10.(canceled)
 11. The method according to claim 1 wherein said neoplasticcell is an adenoma or an adenocarcinoma. 12-13. (canceled)
 14. Themethod according to claim 1 wherein said control level is anon-neoplastic level. 15-26. (canceled)
 27. The method according to anyone of claim 1, 11, or 14 wherein said cell is a colorectal cell. 28.The method according to any one of claim 1, 11, or 14 wherein saidbiological sample is a faecal sample, enema wash, surgical resection,tissue biopsy or blood sample.
 29. The method according to any one ofclaim 1, 11, or 14 wherein said level of expression is mRNA expressionor protein expression.
 30. The method according to any one of claim 1,11, or 14 wherein said level of expression is assessed by screening forchanges to genomic DNA.
 31. The method according to claim 30 whereinsaid changes to genomic DNA are changes to DNA methylation.
 32. Themethod according to any one of claim 1, 11, or 14 wherein said level ofexpression is assessed by screening for changes to the chromatin proteinwith which said gene is associated.
 33. The method according to any oneof claim 1, 11, or 14 wherein said individual is a human. 34-35.(canceled)